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Sample records for acyclic nucleoside phosphonate

  1. Medicinal chemistry of fluorinated cyclic and acyclic nucleoside phosphonates.

    PubMed

    Baszczyňski, Ondřej; Janeba, Zlatko

    2013-11-01

    The fluorine atom plays an important role in medicinal chemistry because fluorine substitution has a strong impact on the physical, chemical, and biological properties of bioactive compounds. Such fluorine modifications have also been extensively studied among the pharmaceutically important class of nucleoside phosphonates, nucleotide analogues in which the phosphate group is replaced by the enzymatically and chemically stable phosphonate moiety. The fluorinated nucleoside phosphonates abound with antiviral, antiparasitic, and anticancer properties because they are able to act as inhibitors of important enzymes of nucleoside/nucleotide metabolism. In this paper, we review the biological properties of cyclic and acyclic nucleoside phosphonates modified by the attachment of one or more fluorine atoms to various parts of the molecule, namely to nucleobases, alkylphosphonate groups, cyclic or acyclic linkers, or to prodrug moieties. PMID:23893552

  2. N-Branched acyclic nucleoside phosphonates as monomers for the synthesis of modified oligonucleotides.

    PubMed

    Hocková, Dana; Rosenbergová, Šárka; Ménová, Petra; Páv, Ondřej; Pohl, Radek; Novák, Pavel; Rosenberg, Ivan

    2015-04-21

    Protected N-branched nucleoside phosphonates containing adenine and thymine bases were prepared as the monomers for the introduction of aza-acyclic nucleotide units into modified oligonucleotides. The phosphotriester and phosphoramidite methods were used for the incorporation of modified and natural units, respectively. The solid phase synthesis of a series of nonamers containing one central modified unit was successfully performed in both 3'→5' and 5'→3' directions. Hybridization properties of the prepared oligoribonucleotides and oligodeoxyribonucleotides were evaluated. The measurement of thermal characteristics of the complexes of modified nonamers with the complementary strand revealed a considerable destabilizing effect of the introduced units. We also examined the substrate/inhibitory properties of aza-acyclic nucleoside phosphono-diphosphate derivatives (analogues of nucleoside triphosphates) but neither inhibition of human and bacterial DNA polymerases nor polymerase-mediated incorporation of these triphosphate analogues into short DNA was observed. PMID:25766752

  3. Antimalarial activity of prodrugs of N-branched acyclic nucleoside phosphonate inhibitors of 6-oxopurine phosphoribosyltransferases.

    PubMed

    Hocková, Dana; Janeba, Zlatko; Naesens, Lieve; Edstein, Michael D; Chavchich, Marina; Keough, Dianne T; Guddat, Luke W

    2015-09-01

    Acyclic nucleoside phosphonates (ANPs) that contain a 6-oxopurine base are good inhibitors of the human and Plasmodium falciparum 6-oxopurine phosphoribosyltransferases (PRTs), key enzymes of the purine salvage pathway. Chemical modifications, based on the crystal structures of several inhibitors in complex with the human PRTase, led to the design of a new class of inhibitors--the aza-ANPs. Because of the negative charges of the phosphonic acid moiety, their ability to cross cell membranes is, however, limited. Thus, phosphoramidate prodrugs of the aza-ANPs were prepared to improve permeability. These prodrugs arrest parasitemia with IC50 values in the micromolar range against Plasmodium falciparum-infected erythrocyte cultures (both chloroquine-sensitive and chloroquine-resistant Pf strains). The prodrugs exhibit low cytotoxicity in several human cell lines. Thus, they fulfill two essential criteria to qualify them as promising antimalarial drug leads. PMID:26275679

  4. Versatile synthesis of oxime-containing acyclic nucleoside phosphonates--synthetic solutions and antiviral activity.

    PubMed

    Solyev, Pavel N; Jasko, Maxim V; Kleymenova, Alla A; Kukhanova, Marina K; Kochetkov, Sergey N

    2015-11-28

    New oxime-containing acyclic nucleoside phosphonates 9-{2-[(phosphonomethyl)oximino]ethyl}adenine (1), -guanine (2) and 9-{2-[(phosphonomethyl)oximino]propyl}adenine (3) with wide spectrum activity against different types of viruses were synthesized. The key intermediate, diethyl aminooxymethylphosphonate, was obtained by the Mitsunobu reaction. Modified conditions for the by-product separation (without chromatography and distillation) allowed us to obtain 85% yield of the aminooxy intermediate. The impact of DBU and Cs2CO3 on the N(9)/N(7) product ratio for adenine and guanine alkylation was studied. A convenient procedure for aminooxy group detection was found. The synthesized phosphonates were tested and they appeared to display moderate activity against different types of viruses (HIV, herpes viruses in cell cultures, and hepatitis C virus in the replicon system) without toxicity up to 1000 μM. PMID:26383895

  5. Ester prodrugs of acyclic nucleoside thiophosphonates compared to phosphonates: synthesis, antiviral activity and decomposition study.

    PubMed

    Roux, Loïc; Priet, Stéphane; Payrot, Nadine; Weck, Clément; Fournier, Maëlenn; Zoulim, Fabien; Balzarini, Jan; Canard, Bruno; Alvarez, Karine

    2013-05-01

    9-[2-(Thiophosphonomethoxy)ethyl]adenine [S-PMEA, 8] and (R)-9-[2-(Thiophosphonomethoxy)propyl]adenine [S-PMPA, 9] are acyclic nucleoside thiophosphonates we described recently that display the same antiviral spectrum (DNA viruses) as approved and potent phosphonates PMEA and (R)-PMPA. Here, we describe the synthesis, antiviral activities in infected cell cultures and decomposition study of bis(pivaloyloxymethoxy)-S-PMEA [Bis-POM-S-PMEA, 13] and bis(isopropyloxymethylcarbonyl)-S-PMPA [Bis-POC-S-PMPA, 14] as orally bioavailable prodrugs of the S-PMEA 8 and S-PMPA 9, in comparison to the equivalent "non-thio" derivatives [Bis-POM-PMEA, 11] and [Bis-POC-PMPA, 12]. Compounds 11, 12, 13 and 14 were evaluated for their in vitro antiviral activity against HIV-1-, HIV-2-, HBV- and a broad panel of DNA viruses, and found to exhibit moderate to potent antiviral activity. In order to determine the decomposition pathway of the prodrugs 11, 12, 13 and 14 into parent compounds PMEA, PMPA, 8 and 9, kinetic data and decomposition pathways in several media are presented. As expected, bis-POM-S-PMEA 13 and bis-POC-S-PMPA 14 behaved as prodrugs of S-PMEA 8 and S-PMPA 9. However, thiophosphonates 8 and 9 were released very smoothly in cell extracts, in contrast to the release of PMEA and PMPA from "non-thio" prodrugs 11 and 12. PMID:23603046

  6. A new class of acyclic nucleoside phosphonates: synthesis and biological activity of 9-[[(phosphonomethyl)aziridin-1-yl]methyl]guanine (PMAMG) and analogues.

    PubMed

    Abu Sheikha, Ghassan; La Colla, Paolo; Loi, Anna Giulia

    2002-10-01

    A new class of acyclic nucleoside phosphonates PMAMG, PMAMA, PMAMC, and PMAMT (compounds 1, 2, 3 and 4) have been synthesized and tested in vitro against a wide variety of viruses, fungi and bacteria. PMAMG (1) was synthesized by the alkylation reaction of acetylguanine with the phosphonate side-chain, diisopropyl [[2-(bromomethyl)aziridin-1-yl

  7. Synthesis and Evaluation of Novel Acyclic Nucleoside Phosphonates as Inhibitors of Plasmodium falciparum and Human 6-Oxopurine Phosphoribosyltransferases.

    PubMed

    Kaiser, Martin M; Hocková, Dana; Wang, Tzu-Hsuan; Dračínský, Martin; Poštová-Slavětínská, Lenka; Procházková, Eliška; Edstein, Michael D; Chavchich, Marina; Keough, Dianne T; Guddat, Luke W; Janeba, Zlatko

    2015-10-01

    Acyclic nucleoside phosphonates (ANPs) are a promising class of antimalarial therapeutic drug leads that exhibit a wide variety of Ki values for Plasmodium falciparum (Pf) and human hypoxanthine-guanine-(xanthine) phosphoribosyltransferases [HG(X)PRTs]. A novel series of ANPs, analogues of previously reported 2-(phosphonoethoxy)ethyl (PEE) and (R,S)-3-hydroxy-2-(phosphonomethoxy)propyl (HPMP) derivatives, were designed and synthesized to evaluate their ability to act as inhibitors of these enzymes and to extend our ongoing antimalarial structure-activity relationship studies. In this series, (S)-3-hydroxy-2-(phosphonoethoxy)propyl (HPEP), (S)-2-(phosphonomethoxy)propanoic acid (CPME), or (S)-2-(phosphonoethoxy)propanoic acid (CPEE) are the acyclic moieties. Of this group, (S)-3-hydroxy-2-(phosphonoethoxy)propylguanine (HPEPG) exhibits the highest potency for PfHGXPRT, with a Ki value of 0.1 μM and a Ki value for human HGPRT of 0.6 μM. The crystal structures of HPEPG and HPEPHx (where Hx=hypoxanthine) in complex with human HGPRT were obtained, showing specific interactions with active site residues. Prodrugs for the HPEP and CPEE analogues were synthesized and tested for in vitro antimalarial activity. The lowest IC50 value (22 μM) in a chloroquine-resistant strain was observed for the bis-amidate prodrug of HPEPG. PMID:26368337

  8. Acyclic nucleoside phosphonates with 5-azacytosine base moiety substituted in C-6 position.

    PubMed

    Krecmerová, Marcela; Masojídková, Milena; Holý, Antonín

    2010-01-01

    Two methods for preparation of 6-substituted derivatives of anti DNA-viral agent 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine (HPMP-5-azaC) were developed: (1) ammonia mediated ring-opening reaction of diisopropyl esters of HPMP-5-azaC (4) to carbamoylguanidine derivatives followed by ring-closure reaction with orthoesters and (2) condensation reaction of 6-substituted 5-azacytosines with diisopropyl (1S)-[2-hydroxy-1-tosyloxymethyl)ethoxy]methylphosphonate (15). Deprotection of diisopropyl esters to free phosphonic acids was performed with bromotrimethylsilane in acetonitrile followed by hydrolysis. In contrast to parent compound HPMP-5-azaC, a substantial decrease of antiviral activity in case of 6-substituted analogues occurred. Surprisingly, N-3 isomer of 6-methyl-HPMP-5-azaC in the form of isopropyl ester revealed activity against RNA viruses (Sindbis virus). PMID:19914075

  9. Acyclic nucleoside/nucleotide analogues with an imidazole ring skeleton.

    PubMed

    Chen, H M; Hosmane, R S

    2001-08-01

    Syntheses of a few acyclic nucleoside and acyclic nucleoside phosphonate analogues containing an imidazole ring have been reported. These analogues include methyl 1-(2-hydroxyethoxymethyl)imidazole-4, 5-dicarbo-xylate (1), 4,5-dicarbamoyl-1-(2-hydroxyethoxymethyl)imidazole (2), 4,5-dicyano-1-(2-hydroxyethoxymethyl)imidazole (4), Methyl 1-(2-bromoethoxymethyl)imidazole-4,5-dicarboxylate (7), 4,5-dicyano-(2-bromoethoxymethyl)imidazole (8), and Methyl 1-(2-phosphonomethoxyethyl)imidazole (10). Also reported are a few potential prodrugs of the above compounds, including the acetyl derivatives 5 and 6 (of 1 and 4, respectively), and the diethyl phosphonate ester 9 (of 10). In addition, the corresponding benzyl-protected precursors 11 and 12 (of 1 and 4, respectively), along with their common hydrolysis product, 1-(2-benzyloxy-ethoxymethyl)-4,5-imidazoledicarboxylic acid (3), are reported. Another potential prodrug included in the list is 1-(2-acetoxyethyl)-4,5-dicyanoimidazole (15). The compounds were screened for in vitro antiviral activity against a wide variety of herpes and respiratory viruses. The most active compound was the phosphonate analogue 9 which exhibited an anti-measles virus activity with an EC50 of <2.5 microg/mL and an SI value of > 176. PMID:11554548

  10. Alpha-carboxy nucleoside phosphonates as universal nucleoside triphosphate mimics

    PubMed Central

    Balzarini, Jan; Das, Kalyan; Bernatchez, Jean A.; Martinez, Sergio E.; Ngure, Marianne; Keane, Sarah; Ford, Alan; Maguire, Nuala; Mullins, Niki; John, Jubi; Kim, Youngju; Dehaen, Wim; Vande Voorde, Johan; Liekens, Sandra; Naesens, Lieve; Götte, Matthias; Maguire, Anita R.; Arnold, Eddy

    2015-01-01

    Polymerases have a structurally highly conserved negatively charged amino acid motif that is strictly required for Mg2+ cation-dependent catalytic incorporation of (d)NTP nucleotides into nucleic acids. Based on these characteristics, a nucleoside monophosphonate scaffold, α-carboxy nucleoside phosphonate (α-CNP), was designed that is recognized by a variety of polymerases. Kinetic, biochemical, and crystallographic studies with HIV-1 reverse transcriptase revealed that α-CNPs mimic the dNTP binding through a carboxylate oxygen, two phosphonate oxygens, and base-pairing with the template. In particular, the carboxyl oxygen of the α-CNP acts as the potential equivalent of the α-phosphate oxygen of dNTPs and two oxygens of the phosphonate group of the α-CNP chelate Mg2+, mimicking the chelation by the β- and γ-phosphate oxygens of dNTPs. α-CNPs (i) do not require metabolic activation (phosphorylation), (ii) bind directly to the substrate-binding site, (iii) chelate one of the two active site Mg2+ ions, and (iv) reversibly inhibit the polymerase catalytic activity without being incorporated into nucleic acids. In addition, α-CNPs were also found to selectively interact with regulatory (i.e., allosteric) Mg2+-dNTP-binding sites of nucleos(t)ide-metabolizing enzymes susceptible to metabolic regulation. α-CNPs represent an entirely novel and broad technological platform for the development of specific substrate active- or regulatory-site inhibitors with therapeutic potential. PMID:25733891

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

    SciTech Connect

    Hazelton, Keith Z.; Ho, Meng-Chaio; Cassera, Maria B.; Clinch, Keith; Crump, Douglas R.; Rosario Jr., Irving; Merino, Emilio F.; Almo, Steve C.; Tyler, Peter C.; Schramm, Vern L.

    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.

  12. Synthesis of Methylenecyclopropane Analogues of Antiviral Nucleoside Phosphonates

    PubMed Central

    Yan, Zhaohua; Zhou, Shaoman; Kern, Earl R.; Zemlicka, Jiri

    2006-01-01

    Synthesis of methylenecyclopropane analogues of nucleoside phosphonates 6a, 6b, 7a and 7b is described. Cyclopropyl phosphonate 8 was transformed in four steps to methylenecyclopropane phosphonate 16. The latter intermediate was converted in seven steps to the key Z- and E-methylenecyclopropane alcohols 23 and 24 separated by chromatography. Selenoxide eliminations (15 → 16 and 22 → 23 + 24) were instrumental in the synthesis. The Z- and E-isomers 23 and 24 were transformed to bromides 25a and 25b which were used for alkylation of adenine and 2-amino-6-chloropurine to give intermediates 26a, 26b, 26c and 26d. Acid hydrolysis provided the adenine and guanine analogues 6a, 6b, 7a and 7b. Phosphonates 6b and 7b are potent inhibitors of replication of Epstein-Barr virus (EBV). PMID:16758001

  13. Synthesis of α-L-threose nucleoside phosphonates via regioselective sugar protection.

    PubMed

    Dumbre, Shrinivas G; Jang, Mi-Yeon; Herdewijn, Piet

    2013-07-19

    A new synthesis route to α-L-threose nucleoside phosphonates via 2-O and 3-O selectively protected L-threose is developed. The key intermediates 2-O-benzoyl-L-threonolactone and 1-O-acetyl-2-O-benzoyl-3-O-t-butyldiphenylsilyl-L-threofuranose were functionalized to synthesize 2'-deoxy-2'-fluoro- and 3'-C-ethynyl L-threose 3'-O-phosphonate nucleosides. The key intermediates developed are important intermediates for the synthesis of new L-threose-based nucleoside analogues, TNA phosphoramidites, and TNA triphosphates. PMID:23822647

  14. Acyclic phosph(on)ate inhibitors of Plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase

    PubMed Central

    Clinch, Keith; Crump, Douglas R.; Evans, Gary B.; Hazleton, Keith Z.; Mason, Jennifer M.; Schramm, Vern L.

    2013-01-01

    The pathogenic protozoa responsible for malaria lack enzymes for the de novo synthesis of purines and rely on purine salvage from the host. In Plasmodium falciparum (Pf), hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) converts hypoxanthine to inosine monophosphate and is essential for purine salvage making the enzyme an anti-malarial drug target. We have synthesized a number of simple acyclic aza-C- nucleosides and shown that some are potent inhibitors of Pf HGXPRT while showing excellent selectivity for the Pf versus the human enzyme. PMID:23810424

  15. Synthesis of phosphonate analogues of the antiviral cyclopropane nucleoside A-5021.

    PubMed

    Onishi, Tomoyuki; Sekiyama, Takaaki; Tsuji, Takashi

    2005-01-01

    A series of phosphonate analogues of the antiviral cyclopropane nucleoside A-5021 were synthesized from (1S*, 7R*)-3,5-dioxa-4,4-diphenylbicyclo[5. 1.0]octane-l-methanol by a 10-step process. In contrast to the potent antiherpetic activity of A-5021, they were all devoid of antiviral activity. PMID:16270661

  16. A new strategy to construct acyclic nucleosides via Ag(I)-catalyzed addition of pronucleophiles to 9-allenyl-9H-purines.

    PubMed

    Wei, Tao; Xie, Ming-Sheng; Qu, Gui-Rong; Niu, Hong-Ying; Guo, Hai-Ming

    2014-02-01

    A new strategy to construct acyclic nucleosides with diverse side chains was developed. With Ag(I) salts as catalysts, the hydrocarboxylation, hydroamination, and hydrocarbonation reactions proceeded well, affording acyclic nucleosides in good yields (41 examples, 60-98% yields). Meanwhile, these reactions exhibited high chemoselectivities and E-selectivities. PMID:24437554

  17. Novel carboranyl derivatives of nucleoside mono- and diphosphites and phosphonates: a synthetic investigation.

    PubMed

    Vyakaranam, Kamesh; Hosmane, Narayan S

    2004-01-01

    A number of nucleoside mono- and diphosphites and phosphonates containing 1,2-dicarbadodecaborane (12) (la-6b) at 5'-position of the sugar moiety have been synthesized in good yields. Experimental details along with the spectroscopic and analytical data, supporting the formation of the title compounds, are presented. These constitute a new generation of boron compounds that are envisioned to be useful in cancer treatment via Boron Neutron Capture Therapy (BNCT). PMID:18365067

  18. Diversity-oriented synthesis of acyclic nucleosides via ring-opening of vinyl cyclopropanes with purines.

    PubMed

    Niu, Hong-Ying; Du, Cong; Xie, Ming-Sheng; Wang, Yong; Zhang, Qian; Qu, Gui-Rong; Guo, Hai-Ming

    2015-02-25

    The diversity-oriented synthesis of acyclic nucleosides has been achieved via ring-opening of vinyl cyclopropanes with purines. With Pd2(dba)3·CHCl3 as a catalyst, the 1,5-ring-opening reaction proceeded well and afforded N9 adducts as the major form, in which the C=C bonds in the side chain were exclusively E-form. In the presence of AlCl3, the 1,3-ring-opening reaction occurred smoothly, giving N9 adducts as the dominate products. Meanwhile, when MgI2 was used as the catalyst, the 1,3-ring-opening reaction also worked well to form N7 adducts. PMID:25572827

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

    PubMed

    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

  20. Synthesis and antiviral activity of novel acyclic nucleoside analogues of 5-(1-azido-2-haloethyl)uracils.

    PubMed

    Kumar, R; Sharma, N; Nath, M; Saffran, H A; Tyrrell, D L

    2001-11-22

    We present the discovery of a novel category of 5-substituted acyclic pyrimidine nucleosides as potent antiviral agents. A series of 1-[(2-hydroxyethoxy)methyl] (5-7), 1-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl] (8-10), and 1-[4-hydroxy-3-(hydroxymethyl)-1-butyl] (11-13) derivatives of 5-(1-azido-2-haloethyl)uracil were synthesized and evaluated for their biological activity in cell culture. 1-[4-Hydroxy-3-(hydroxymethyl)-1-butyl]-5-(1-azido-2-chloroethyl)uracil (12) was the most effective antiviral agent in the in vitro assays against DHBV (EC(50) = 0.31-1.55 microM) and HCMV (EC(50) = 3.1 microM). None of the compounds investigated showed any detectable toxicity to several stationary and proliferating host cells. PMID:11708924

  1. Enzymatic synthesis of acyclic nucleoside thiophosphonate diphosphates: effect of the α-phosphorus configuration on HIV-1 RT activity.

    PubMed

    Priet, Stéphane; Roux, Loic; Saez-Ayala, Magali; Ferron, François; Canard, Bruno; Alvarez, Karine

    2015-05-01

    The acyclic nucleosides thiophosphonates (9-[2-(thiophosphonomethoxy)ethyl]adenine (S-PMEA) and (R)-9-[2-(thiophosphonomethoxy)propyl]adenine (S-PMPA), exhibit antiviral activity against HIV-1, -2 and HBV. Their diphosphate forms S-PMEApp and S-PMPApp, synthesized as stereoisomeric mixture, are potent inhibitors of wild-type (WT) HIV-1 RT. Understanding HIV-1 RT stereoselectivity, however, awaits resolution of the diphosphate forms into defined stereoisomers. To this aim, thiophosphonate monophosphates S-PMEAp and S-PMPAp were synthesized and used in a stereocontrolled enzyme-catalyzed phosphoryl transfer reaction involving either nucleoside diphosphate kinase (NDPK) or creatine kinase (CK) to obtain thiophosphonate diphosphates as separated isomers. We then quantified substrate preference of recombinant WT HIV-1 RT toward pure stereoisomers using in vitro steady-state kinetic analyses. The crystal structure of a complex between Dictyostelium NDPK and S-PMPApp at 2.32Å allowed to determine the absolute configuration at the α-phosphorus atom in relation to the stereo-preference of studied enzymes. The RP isomer of S-PMPApp and S-PMEApp are the preferred substrate over SP for both NDPK and HIV-1 RT. PMID:25766862

  2. Design and synthesis of novel 5-substituted acyclic pyrimidine nucleosides as potent and selective inhibitors of hepatitis B virus.

    PubMed

    Kumar, Rakesh; Nath, Mahendra; Tyrrell, D Lorne J

    2002-05-01

    A novel class of 5-substituted acyclic pyrimidine nucleosides, 1-[(2-hydroxyethoxy)methyl]-5-(1-azidovinyl)uracil (9a), 1-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl]-5-(1-azidovinyl)uracil (9b), and 1-[4-hydroxy-3-(hydroxymethyl)-1-butyl]-5-(1-azidovinyl)uracil (9c), were synthesized by regiospecific addition of bromine azide to the 5-vinyl substituent of the respective 5-vinyluracils (2a-c) followed by treatment of the obtained 5-(1-azido-2-bromoethyl) compounds (3a-c) with t-BuOK, to affect the base-catalyzed elimination of HBr. Thermal decomposition of 9b and 9c at 110 degrees C in dioxane yielded corresponding 5-[2-(1-azirinyl)]uracil analogues (10b,c). The 5-(1-azidovinyl)uracil derivatives 9a-c were found to exhibit potent and selective in vitro anti-HBV activity against duck hepatitis B virus (DHBV) infected primary duck hepatocytes at low concentrations (EC(50) = 0.01-0.1 microg/mL range). The most active anti-DHBV agent (9c), possessing a [4-hydroxy-3-(hydroxymethyl)-1-butyl] substituent at N-1, exhibited an activity (EC(50) of 0.01-0.05 microg/mL) comparable to that of reference compound (-)-beta-L-2',3'-dideoxy-3'-thiacytidine (3-TC) (EC(50) = 0.01-0.05 microg/mL). In contrast, related 5-[2-(1-azirinyl)]uracil analogues (10b,c) were devoid of anti-DHBV activity, indicating that an acyclic side chain at C-5 position of the pyrimidine ring is essential for anti-HBV activity. The pyrimidine nucleosides (9a-c, 10b,c) exhibited no cytotoxic activity against a panel of 60 human cancer cell lines. All of the compounds investigated did not show any detectable toxicity to several stationary and proliferating host cell lines or to mitogen stimulated proliferating human T lymphocytes, up to the highest concentration tested. PMID:11985471

  3. Discovery of GS-9131: Design, synthesis and optimization of amidate prodrugs of the novel nucleoside phosphonate HIV reverse transcriptase (RT) inhibitor GS-9148.

    PubMed

    Mackman, Richard L; Ray, Adrian S; Hui, Hon C; Zhang, Lijun; Birkus, Gabriel; Boojamra, Constantine G; Desai, Manoj C; Douglas, Janet L; Gao, Ying; Grant, Deborah; Laflamme, Genevieve; Lin, Kuei-Ying; Markevitch, David Y; Mishra, Ruchika; McDermott, Martin; Pakdaman, Rowchanak; Petrakovsky, Oleg V; Vela, Jennifer E; Cihlar, Tomas

    2010-05-15

    GS-9148 [(5-(6-amino-purin-9-yl)-4-fluoro-2,5-dihydro-furan-2-yloxymethyl)phosphonic acid] 4 is a novel nucleoside phosphonate HIV-1 reverse transcriptase (RT) inhibitor with a unique resistance profile toward N(t)RTI resistance mutations. To effectively deliver 4 and its active phosphorylated metabolite 15 into target cells, a series of amidate prodrugs were designed as substrates of cathepsin A, an intracellular lysosomal carboxypeptidase highly expressed in peripheral blood mononuclear cells (PBMCs). The ethylalaninyl phosphonamidate prodrug 5 (GS-9131) demonstrated favorable cathepsin A substrate properties, in addition to favorable in vitro intestinal and hepatic stabilities. Following oral dosing (3mg/kg) in Beagle dogs, high levels (>9.0microM) of active metabolite 15 were observed in PBMCs, validating the prodrug design process and leading to the nomination of 5 as a clinical candidate. PMID:20409721

  4. Exploring the role of the α-carboxyphosphonate moiety in the HIV-RT activity of α-carboxy nucleoside phosphonates

    PubMed Central

    Mullins, Nicholas D.; Maguire, Nuala M.; Ford, Alan; Das, Kalyan; Arnold, Edward; Balzarini, Jan; Maguire, Anita R.

    2016-01-01

    As α-carboxy nucleoside phosphonates (α-CNPs) have demonstrated a novel mode of action of HIV-1 reverse transcriptase inhibition, structurally related derivatives were synthesized, namely the malonate 2, the unsaturated and saturated bisphosphonates 3 and 4, respectively and the amide 5. These compounds were evaluated for inhibition of HIV-1 reverse transcriptase in cell-free assays. The importance of the α-carboxy phosphonoacetic acid moiety for achieving reverse transcriptase inhibition, without the need for prior phosphorylation, was confirmed. The malonate derivative 2 was less active by two orders of magnitude than the original α-CNPs, while displaying the same pattern of kinetic behavior; interestingly the activity resides in the “L”-enantiomer of 2, as seen with the earlier series of α-CNPs. A crystal structure with an RT/DNA complex at 2.95 Å resolution revealed the binding of the “L”-enantiomer of 2, at the polymerase active site with a weaker metal ion chelation environment compared to 1a (T-α-CNP) which may explain the lower inhibitory activity of 2. PMID:26813581

  5. Flexibility as a Strategy in Nucleoside Antiviral Drug Design.

    PubMed

    Peters, H L; Ku, T C; Seley-Radtke, K L

    2015-01-01

    As far back as Melville Wolfrom's acyclic sugar synthesis in the 1960's, synthesis of flexible nucleoside analogues have been an area of interest. This concept, however, went against years of enzyme-substrate binding theory. Hence, acyclic methodology in antiviral drug design did not take off until the discovery and subsequent FDA approval of such analogues as Acyclovir and Tenofovir. More recently, the observation that flexible nucleosides could overcome drug resistance spawned a renewed interest in the field of nucleoside drug design. The next generation of flexible nucleosides shifted the focus from the sugar moiety to the nucleobase. With analogues such as Seley-Radtke "fleximers", and Herdewijn's C5 substituted 2'-deoxyuridines, the area of base flexibility has seen great expansion. More recently, the marriage of these methodologies with acyclic sugars has resulted in a series of acyclic flex-base nucleosides with a wide range of antiviral properties, including some of the first to exhibit anti-coronavirus activity. Various flexible nucleosides and their corresponding nucleobases will be compared in this review. PMID:26282942

  6. Copper-catalyzed α-amination of phosphonates and phosphine oxides: a direct approach to α-amino phosphonic acids and derivatives.

    PubMed

    McDonald, Stacey L; Wang, Qiu

    2014-02-10

    A direct approach to important α-amino phosphonic acids and its derivatives has been developed by using copper-catalyzed electrophilic amination of α-phosphonate zincates with O-acyl hydroxylamines. This amination provides the first example of CN bond formation which directly introduces acyclic and cyclic amines to the α-position of phosphonates in one step. The reaction is readily promoted at room temperature with as little as 0.5 mol % of catalyst, and demonstrates high efficiency on a broad substrate scope. PMID:24474326

  7. Synthesis and antiviral activity evaluation of acyclic 2'-azanucleosides bearing a phosphonomethoxy function in the side chain.

    PubMed

    Koszytkowska-Stawińska, Mariola; De Clercq, Erik; Balzarini, Jan

    2009-06-01

    Acyclic 2'-azanucleosides with a phosphonomethoxy function in the side chain were obtained by coupling of diethyl {2-[N-(pivaloyloxymethyl)-N-(p-toluenesulfonyl)amino]ethoxymethyl}phosphonate with the pyrimidine nucleobases via the Vorbrüggen-type protocol. The compounds were evaluated in vitro for activity against a broad variety of RNA and DNA viruses. PMID:19442526

  8. A model study directed towards the preparation of nucleopeptides via H-phosphonate intermediates.

    PubMed Central

    Kuyl-Yeheskiely, E; Tromp, C M; Schaeffer, A H; van der Marel, G A; van Boom, J H

    1987-01-01

    The monofunctional phosphitylating reagents bis-(N,N-diethylamino)chlorophosphine and salicylchlorophosphine have been applied for the preparation of H-phosphonates of the amino acids serine, threonine and tyrosine. Experimental evidence showed that the latter reagent was less effective for the synthesis of a tyrosine H-phosphonate. The amino acids (peptide) H-phosphonates of serine or threonine proved to be suitable starting compounds for the formation of a phosphate diester bond with the 5'-OH of a d-nucleoside derivative using pivaloyl chloride as the activating reagent. PMID:3103103

  9. New phosphonate reagents for aldehyde homologation

    Technology Transfer Automated Retrieval System (TEKTRAN)

    New phosphonate reagents were developed for the two-carbon homologation of aldehydes to unbranched- or methyl-branched unsaturated aldehydes. The phosphonate reagents, diethyl methylformyl-2-phosphonate dimethylhydrazone and diethyl ethylformyl-2-phosphonate dimethylhydrazone, contained a protected...

  10. Nucleoside transport in primary cultured rabbit tracheal epithelial cells.

    PubMed

    Mathias, Neil R; Wu, Sharon K; Kim, Kwang-Jin; Lee, Vincent H L

    2005-01-01

    The present study aimed at elucidating the mechanisms of nucleoside transport in primary cultured rabbit tracheal epithelial cells (RTEC) grown on a permeable filter support. Uptake of (3)H-uridine, the model nucleoside substrate, from the apical fluid of primary cultured RTEC was examined with respect to its dependence on Na(+), substrate concentration, temperature and its sensitivity to inhibitors, other nucleosides and antiviral nucleoside analogs. Apical (3)H-uridine uptake in primary cultured RTEC was strongly dependent on an inward Na(+) gradient and temperature. Ten micromolar nitro-benzyl-mercapto-purine-ribose (NBMPR) (an inhibitor of es-type nucleoside transport in the nanomolar range) did not further inhibit this process. (3)H-uridine uptake from apical fluid was inhibited by basolateral ouabain (10 microM) and apical phloridzin (100 microM), indicating that uptake may involve a secondary active transport process. Uridine uptake was saturable with a K(m) of 3.4 +/- 1.8 microM and the V(max) of 24.3 +/- 5.2 pmoles/mg protein/30 s. Inhibition studies indicated that nucleoside analogs that have a substitution on the nucleobase competed with uridine uptake from apical fluid, but those with modifications on the ribose sugar including acyclic analogs were ineffective. The pattern of inhibition of apical (3)H-uridine, (3)H-inosine and (3)H-thymidine uptake into RTEC cells by physiological nucleosides was consistent with multiple systems: A pyrimidine-selective transport system (CNT1); a broad nucleoside substrate transport system that excludes inosine (CNT4) and an equilibrative NBMPR-insensitive nucleoside transport system (ei type). These results indicate that the presence of apically located nucleoside transporters in the epithelial cells lining the upper respiratory tract can lead to a high accumulation of nucleosides in the trachea. At least one Na(+)-dependent, secondary, active transport process may mediate the apical absorption of nucleosides or

  11. Copper-catalyzed asymmetric synthesis of tertiary α-hydroxy phosphonic acid derivatives with in situ generated nitrosocarbonyl compounds as the oxygen source.

    PubMed

    Maji, Biplab; Yamamoto, Hisashi

    2014-12-22

    α-Hydroxy phosphonic acids and their derivatives are highly bioactive structural motifs. It is now reported that these compounds can be accessed through the copper-catalyzed direct α-oxidation of β-ketophosphonates using in situ generated nitrosocarbonyl compounds as an electrophilic oxygen source. These reactions proceeded in high yields (up to 95 %) and enantioselectivities (up to >99 % ee) for both cyclic as well as acyclic substrates. This method was also applied for the synthesis of α,β-dihydroxy phosphonates and β-amino-α-hydroxy phosphonates. PMID:25348199

  12. Membrane-permeable Triphosphate Prodrugs of Nucleoside Analogues.

    PubMed

    Gollnest, Tristan; Dinis de Oliveira, Thiago; Rath, Anna; Hauber, Ilona; Schols, Dominique; Balzarini, Jan; Meier, Chris

    2016-04-18

    The metabolic conversion of nucleoside analogues into their triphosphates often proceeds insufficiently. Rate-limitations can be at the mono-, but also at the di- and triphosphorylation steps. We developed a nucleoside triphosphate (NTP) delivery system (TriPPPro-approach). In this approach, NTPs are masked by two bioreversible units at the γ-phosphate. Using a procedure involving H-phosphonate chemistry, a series of derivatives bearing approved, as well as potentially antivirally active, nucleoside analogues was synthesized. The enzyme-triggered delivery of NTPs was demonstrated by pig liver esterase, in human T-lymphocyte cell extracts and by a polymerase chain reaction using a prodrug of thymidine triphosphate. The TriPPPro-compounds of some HIV-inactive nucleoside analogues showed marked anti-HIV activity. For cellular uptake studies, a fluorescent TriPPPro-compound was prepared that delivered the triphosphorylated metabolite to intact CEM cells. PMID:27008042

  13. Generation and exploitation of acyclic azomethine imines in chiral Brønsted acid catalysis

    NASA Astrophysics Data System (ADS)

    Hashimoto, Takuya; Kimura, Hidenori; Kawamata, Yu; Maruoka, Keiji

    2011-08-01

    Successful implementation of a catalytic asymmetric synthesis strategy to produce enantiomerically enriched compounds requires the adoption of suitable prochiral substrates. The combination of an azomethine imine electrophile with various nucleophiles could give straightforward access to a number of synthetically useful chiral hydrazines, but is used rarely. Here we report the exploitation of acyclic azomethine imines as a new type of prochiral electrophile. They can be generated in situ by the condensation of N‧-benzylbenzoylhydrazide with a variety of aldehydes in the presence of a catalytic amount of an axially chiral dicarboxylic acid. By trapping these electrophiles with alkyl diazoacetate or (diazomethyl)phosphonate nucleophiles, we produced a diverse array of chiral α-diazo-β-hydrazino esters and phosphonates with excellent enantioselectivities.

  14. The structure of cyclic nucleoside phosphonate ester prodrugs: an inquiry

    PubMed Central

    Krylov, Ivan S.; Zakharova, Valeria M.; Serpi, Michaela; Haiges, Ralf; Kashemirov, Boris A.; McKenna, Charles E.

    2011-01-01

    The configuration at phosphorus in cyclic (S)-HPMPC (1, Cidofovir) and (S)-HPMPA (2) phenyl ester (5 and 6, respectively) diastereomers ((Rp)-5, (Rp)-6, (Sp)-6) were determined by X-ray crystallography and correlated to their 1H and 31P NMR spectra in solution. (Rp)-5 and (Rp)-6 have chair conformations with the nucleobase substituent equatorial and the P-OPh axial. Perhaps surprisingly, (Sp)-6 is (a, a) in the crystal and exists largely as an equilibrium of (a, a)/ (e, e) conformers in chloroform or acetonitrile. PMID:22126969

  15. Acyclic colorings of graphs with bounded degree

    NASA Astrophysics Data System (ADS)

    Fiedorowicz, Anna; Sidorowicz, Elżbieta

    2016-07-01

    A $k$-colouring (not necessarily proper) of vertices of a graph is called {\\it acyclic}, if for every pair of distinct colours $i$ and $j$ the subgraph induced by the edges whose endpoints have colours $i$ and $j$ is acyclic. In the paper we consider some generalised acyclic $k$-colourings, namely, we require that each colour class induces an acyclic or bounded degree graph. Mainly we focus on graphs with maximum degree 5. We prove that any such graph has an acyclic $5$-colouring such that each colour class induces an acyclic graph with maximum degree at most 4. We prove that the problem of deciding whether a graph $G$ has an acyclic 2-colouring in which each colour class induces a graph with maximum degree at most 3 is NP-complete, even for graphs with maximum degree 5. We also give a linear-time algorithm for an acyclic $t$-improper colouring of any graph with maximum degree $d$ assuming that the number of colors is large enough.

  16. Homochiral metal phosphonate nanotubes.

    PubMed

    Liu, Xun-Gao; Bao, Song-Song; Huang, Jian; Otsubo, Kazuya; Feng, Jian-Shen; Ren, Min; Hu, Feng-Chun; Sun, Zhihu; Zheng, Li-Min; Wei, Shiqiang; Kitagawa, Hiroshi

    2015-10-21

    A new type of homochiral metal-organic nanotubular structures based on metal phosphonates are reported, namely, (R)- or (S)-[M(pemp)(H2O)2][M = Co(II) (1), Ni(II) (2)] [pemp(2-) = (R)- or (S)-(1-phenylethylamino)methylphosphonate]. In these compounds, the tube-walls are purely inorganic, composed of metal ions and O-P-O bridges. The cavity of the nanotube is hydrophilic with one coordination water pointing towards the center, while the outer periphery of the nanotube is hydrophobic, decorated by the phenylethyl groups of pemp(2-). The thermal stabilities, adsorption and proton conductivity properties are investigated. PMID:26324662

  17. Cardioleader use in acyclic types of sports

    NASA Technical Reports Server (NTRS)

    Bondin, V. I.

    1980-01-01

    The use of the cardioleader method in regulating training loads and tests for athletes in acyclic sports was investigated. It was found that the use of this method increases the effectiveness of the training process.

  18. Polymerization of the cyclic pyrophosphates of nucleosides and their analogues

    NASA Technical Reports Server (NTRS)

    Tohidi, Mahrokh; Orgel, Leslie E.

    1990-01-01

    When 2-prime-deoxythymidine 3-prime, 5-prime-cyclic diphosphate, or the cyclic pyrophosphates of the acyclic nucleoside analogs II and IV are heated to 65-85 C in the presence of imidazole, oligomers with lengths up to 20-30 are formed in excellent yield. This reaction provides a useful source of oligomers for use as templates in aqueous condensation reactions. In the absence of evidence to the contrary, it is assumed that the oligomers are atactic. The potential significance of this reaction in prebiotic chemistry is discussed.

  19. Multicomponent reactions in nucleoside chemistry

    PubMed Central

    Buchowicz, Włodzimierz

    2014-01-01

    Summary This review covers sixty original publications dealing with the application of multicomponent reactions (MCRs) in the synthesis of novel nucleoside analogs. The reported approaches were employed for modifications of the parent nucleoside core or for de novo construction of a nucleoside scaffold from non-nucleoside substrates. The cited references are grouped according to the usually recognized types of the MCRs. Biochemical properties of the novel nucleoside analogs are also presented (if provided by the authors). PMID:25161730

  20. Biodegradation of acyclic isoprenoids by Pseudomonas species.

    PubMed Central

    Cantwell, S G; Lau, E P; Watt, D S; Fall, R R

    1978-01-01

    The ability of various pseudomonads to utilize acyclic isoprenoids as a sole carbon source was investigated. Tests for utilization of acyclic isoprenols such as citronellol and geraniol were complicated by toxic effects of these alcohols, and most species tested were killed by exposure to citronellol or geraniol (0.1%, vol/vol) in liquid culture. In the case of Pseudomonas citronellolis, sensitivity to isoprenols is reduced by prior induction of the isoprenoid degradative pathway via either growth on succinate in the presence of citronellol or growth on citronellic acid. For this species, citronellic acid proved to be the best isoprenoid growth substrate tested. Geraniol utilization as a taxonomic indicator for different subgroups of pseudomonads is discussed. Only a few of the species tested were able to utilize acyclic isoprenoids. Two species which utilize C10 acyclic isoprenoids, P. aeruginosa and P. mendocina, were shown to contain the inducible enzyme geranyl-coenzyme A carboxylase, one of the unique enzymes in the isoprenol degradative pathway known to occur in P. citronellolis. Of the species which utilized geranitol, none showed definite growth on the homologous C15 and C20 isoprenols. PMID:681275

  1. Phosphonate derivatives of Methyl oleate

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Phosphorus-containing compounds are often incorporated in lubricants and plastic to improve their properties. In lubricants, phosphonates or diphosphites improve the oxidative stability, anti-wear and extreme pressure properties. In the current work, we describe the synthesis and characterization ...

  2. Isopropyl methyl phosphonic acid (IMPA)

    Integrated Risk Information System (IRIS)

    Isopropyl methyl phosphonic acid ( IMPA ) ; CASRN 1832 - 54 - 8 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assess

  3. Synthesis and hybridization properties of an acyclic achiral phosphonate DNA analogue.

    PubMed

    Kehler, J; Henriksen, U; Vejbjerg, H; Dahl, O

    1998-03-01

    Protected N-(2-hydroxyethyl)-N-(nucleobase-acetyl)aminomethanephosphonic+ ++ acid (6a-d) of all four DNA nucleobases have been prepared and oligomerized by solid-phase synthesis. Four DNA decamers containing 1-10 of these 'PPNA' monomers were prepared and evaluated by Tm measurements (medium salt) for binding to their DNA and RNA complements. One central modification reduced the binding strongly (delta Tm = -10 degrees C), but contiguous PPNA monomers gave smaller effects, and the all-PPNA decamer bound to RNA with a delta Tm of -1.2 degrees C per modification. Thus PPNA oligomers are inferior DNA and RNA binders compared to the closely related and strongly binding PNA oligomers. PMID:9568285

  4. Development of a Diastereoselective Phosphorylation of a Complex Nucleoside via Dynamic Kinetic Resolution.

    PubMed

    Tran, Kristy; Beutner, Gregory L; Schmidt, Michael; Janey, Jacob; Chen, Ke; Rosso, Victor; Eastgate, Martin D

    2015-05-15

    The development of a diastereoselective nucleoside phosphorylation is described, which produces a single isomer of a complex nucleoside monophosphate pro-drug. A stable phosphoramidic acid derivative is coupled to the nucleoside, in a process mediated by HATU and quinine, to deliver the coupled product in high chemical yield and good diastereoselectivity. This unusual process was shown to proceed through a dynamic kinetic resolution of a 1:1 mixture of activated phosphonate ester diastereoisomers. The optimized conditions afforded the product with a combined [S,S(P)] and [S,R(P)] in-process yield of 89% and a ∼7:1 [S,S(P):S,R(P)] diastereomeric ratio. Isolation of the major isomer was facilitated by single crystallization from anisole, where the product was obtained in 57% isolated yield, excellent purity (>95%), and a high diastereomeric ratio (>50:1). PMID:25840459

  5. CHARMM Additive All-Atom Force Field for Acyclic Polyalcohols, Acyclic Carbohydrates and Inositol

    PubMed Central

    Hatcher, Elizabeth; Guvench, Olgun; MacKerell, Alexander D.

    2009-01-01

    Parametrization of the additive all-atom CHARMM force field for acyclic polyalcohols, acyclic carbohydrates and inositol is conducted. Initial parameters were transferred from the alkanes and hexopyranose carbohydrates, with subsequent development and optimization of parameters unique to the molecules considered in this study. Using the model compounds acetone and acetaldehyde, nonbonded parameters for carbonyls were optimized targeting quantum mechanical interaction data for solute-water pairs and pure solvent thermodynamic data. Bond and angle parameters were adjusted by comparing optimized geometries to small molecule crystal survey data and by performing vibrational analyses on acetone, acetaldehyde and glycerol. C-C-C-C, C-C-C-O, C-C-OH and O-C-C-O torsional parameters for polyol chains were fit to quantum mechanical dihedral potential energy scans comprising over 1500 RIMP2/cc-pVTZ//MP2/6-31G(d) conformations using an automated Monte Carlo simulated annealing procedure. Comparison of computed condensed-phase data, including crystal lattice parameters and densities, NMR proton-proton couplings, densities and diffusion coefficients of aqueous solutions, to experimental data validated the optimized parameters. Parameter development for these compounds proved particularly challenging because of the flexibility of the acyclic sugars and polyalcohols as well as the intramolecular hydrogen bonding between vicinal hydroxyls for all of the compounds. The newly optimized additive CHARMM force field parameters are anticipated to be of utility for atomic level of detail simulations of acyclic polyalcohols, acyclic carbohydrates and inositol in solution. PMID:20160980

  6. Investigation of diastereoselective acyclic α-alkoxydithioacetal substitutions involving thiacarbenium intermediates.

    PubMed

    Prévost, Michel; Dostie, Starr; Waltz, Marie-Ève; Guindon, Yvan

    2014-11-01

    Reported herein is an experimental and theoretical study that elucidates why silylated nucleobase additions to acyclic α-alkoxythiacarbenium intermediates proceed with high 1,2-syn stereocontrol (anti-Felkin-Anh), which is opposite to what would be expected with corresponding activated aldehydes. The acyclic thioaminals formed undergo intramolecular cyclizations to provide nucleoside analogues with anticancer and antiviral properties. The factors influencing the selectivity of the substitution reaction have been examined thoroughly. Halothioether species initially form, ionize in the presence (low dielectric media) or absence (higher dielectric media) of the nucleophile, and react through SN2-like transition structures (TS A and D), where the α-alkoxy group is gauche to the thioether moiety. An important, and perhaps counterintuitive, observation in this work was that calculations done in the gas phase or low dielectric media (toluene) are essential to locate the product- and rate-determining transition structures (C-N bond formation) that allow the most reasonable prediction of selectivity and isotope effects for more polar solvents (THF, MeCN). The ΔΔG(⧧) (G(TSA-TSD)) obtained in silico are consistent with the preferential formation of 1,2-syn product and with the trends of stereocontrol displayed by 2,3-anti and 2,3-syn α,β-bis-alkoxydithioacetals. PMID:25280088

  7. Transition state analogue inhibitors of human methylthioadenosine phosphorylase and bacterial methylthioadenosine/S-adenosylhomocysteine nucleosidase incorporating acyclic ribooxacarbenium ion mimics

    PubMed Central

    Clinch, Keith; Evans, Gary B.; Fröhlich, Richard F. G.; Gulab, Shivali A.; Gutierrez, Jemy A.; Mason, Jennifer M.; Schramm, Vern L.; Tyler, Peter C.; Woolhouse, Anthony D.

    2012-01-01

    Several acyclic hydroxy-methylthio-amines with 3 to 5 carbon atoms were prepared and coupled via a methylene link to 9-deazaadenine. The products were tested for inhibition against human MTAP and E. coli and N. meningitidis MTANs and gave Ki values as low as 0.23 nM. These results were compared to those obtained with 1st and 2nd generation inhibitors (1S)-1-(9-deazaadenin-9-yl)-1,4-dideoxy-1,4-imino-5-methylthio-d-ribitol (MT-Immucillin-A, 3) and (3R,4S)-1-[9-deazaadenin-9-yl)methyl]3-hydroxy-4-methylthiomethylpyrrolidine (MT-DADMe-Immucillin-A, 4). The best inhibitors were found to exhibit binding affinities of approximately 2- to 4-fold those of 3 but were significantly weaker than 4. Cleavage of the 2,3 carbon–carbon bond in MT-Immucillin-A (3) gave an acyclic product (79) with a 21,500 fold loss of activity against E. coli MTAN. In another case, N-methylation of a side chain secondary amine resulted in a 250-fold loss of activity against the same enzyme [(±)-65 vs (±)-68]. The inhibition results were also contrasted with those acyclic derivatives previously prepared as inhibitors for a related enzyme, purine nucleoside phosphorylase (PNP), where some inhibitors in the latter case were found to be more potent than their cyclic counterparts. PMID:22854195

  8. Synthesis of novel castor oil phosphonates

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  9. Tribological properties of biobased ester phosphonates

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Three phosphonate derivatives of methyl oleate (MeOl) were chemically synthesized in a radical chain reaction and their physical and tribological properties investigated. The three phosphonates differed from each other in the structure of the alkoxy groups attached to the phosphorous, which were as ...

  10. RIBOSE MODIFIED NUCLEOSIDES AND NUCLEOTIDES AS LIGANDS FOR PURINE RECEPTORS

    PubMed Central

    Ravi, R. G.; Nandanan, E.; Kim, H. S.; Moro, S.; Kim, Y. C.; Lee, K.; Barak, D.; Marquez, V. E.; Ji, X. D.

    2016-01-01

    Molecular modeling of receptors for adenosine and nucleotide (P2) receptors with docked ligand, based on mutagenesis, was carried out. Adenosine 3′,5′-bisphosphate derivatives act as selective P2Y1 antagonists/partial agonists. The ribose moiety was replaced with carbocyclics, smaller and larger rings, conformationally constrained rings, and acyclics, producing compounds that retained receptor affinity. Conformational constraints were built into the ribose rings of nucleoside and nucleotide ligands using the methanocarba approach, i.e. fused cyclopropane and cyclopentane rings in place of ribose, suggesting a preference for the Northern (N) conformation among ligands for P2Y1 and A1 and A3ARs. PMID:11563046

  11. Multifunctional p-phosphonated calixarenes.

    PubMed

    Martin, Adam D; Raston, Colin L

    2011-09-21

    p-Phosphonic acid calix[n]arenes and their O-alkylated lower rim analogues are remarkably versatile macrocycles, with applications in selective diameter uptake of single walled carbon nano-tubes, as surfactants in stabilising and protecting nano-particles and graphene sheets, as crystal growth modifiers for inorganic systems, in encapsulating molecules of anti-cancer carboplatin, self assembly into nano-arrays, including nano-fibres and molecular capsules, and for binding metal ions including biologically relevant Ca(2+). They are readily accessible via five or six high yielding steps from the parent p-Bu(t) substituted compounds. PMID:21629880

  12. Crystal structure of calf spleen purine nucleoside phosphorylase with two full trimers in the asymmetric unit: important implications for the mechanism of catalysis.

    PubMed

    Bzowska, Agnieszka; Koellner, Gertraud; Wielgus-Kutrowska, Beata; Stroh, Albrecht; Raszewski, Grzegorz; Holý, Antonin; Steiner, Thomas; Frank, Joachim

    2004-09-17

    The crystal structure of the binary complex of trimeric purine nucleoside phosphorylase (PNP) from calf spleen with the acyclic nucleoside phosphonate inhibitor 2,6-diamino-(S)-9-[2-(phosphonomethoxy)propyl]purine ((S)-PMPDAP) is determined at 2.3A resolution in space group P2(1)2(1)2(1). Crystallization in this space group, which is observed for the first time with a calf spleen PNP crystal structure, is obtained in the presence of calcium atoms. In contrast to the previously described cubic space group P2(1)3, two independent trimers are observed in the asymmetric unit, hence possible differences between monomers forming the biologically active trimer could be detected, if present. Such differences would be expected due to third-of-the-sites binding documented for transition-state events and inhibitors. However, no differences are noted, and binding stoichiometry of three inhibitor molecules per enzyme trimer is observed in the crystal structure, and in the parallel solution studies using isothermal titration calorimetry and spectrofluorimetric titrations. Presence of phosphate was shown to modify binding stoichiometry of hypoxanthine. Therefore, the enzyme was also crystallized in space group P2(1)2(1)2(1) in the presence of (S)-PMPDAP and phosphate, and the resulting structure of the binary PNP/(S)-PMPDAP complex was refined at 2.05A resolution. No qualitative differences between complexes obtained with and without the presence of phosphate were detected, except for the hydrogen bond contact of Arg84 and a phosphonate group, which is observed only in the former complex in three out of six independent monomers. Possible hydrogen bonds observed in the enzyme complexed with (S)-PMPDAP, in particular a putative hydrogen bonding contact N(1)-H cdots, three dots, centered Glu201, indicate that the inhibitor binds in a tautomeric or ionic form in which position N(1) acts as a hydrogen bond donor. This points to a crucial role of this hydrogen bond in defining

  13. Phosphonate analogue substrates for enolase.

    PubMed

    Anderson, V E; Cleland, W W

    1990-11-20

    Phosphonate analogues in which the bridge between C-2 and phosphorus is a CH2 group are slow substrates for yeast enolase. The pH variation of the kinetic parameters for the methylene analogue of 2-phosphoglycerate suggests that the substrate binds as a dianion and that Mg2+ can bind subsequently only if a metal ligand and the catalytic base are unprotonated. Primary deuterium isotope effects of 4-8 on V/KMg, but ones of only 1.15-1.32 on V for dehydration, show that proton removal to give the carbanion intermediate largely limits V/KMg and that a slow step follows which largely limits V (presumably carbanion breakdown). Since there is a D2O solvent isotope effect on V for the reverse reaction of 5, but not an appreciable one on the forward reaction, it appears that the slow rates with phosphonate analogues result from the fact that the carbanion intermediate is more stable than that formed from the normal substrates, and its reaction in both directions limits V. Increased stability as a result of replacement of oxygen by carbon at C-2 of the carbanion is the expected chemical behavior. PMID:2271661

  14. Selective Inhibition of Porcine Endogenous Retrovirus Replication in Human Cells by Acyclic Nucleoside Phosphonates▿

    PubMed Central

    Shi, Minyi; Wang, Xin; De Clercq, Erik; Takao, Sonshin; Baba, Masanori

    2007-01-01

    Several anti-human immunodeficiency virus type 1 reverse transcriptase inhibitors were evaluated for their antiviral activities against porcine endogenous retrovirus in human cells. Among the test compounds, zidovudine was found to be the most active. The order of potency was zidovudine > phosphonylmethoxyethoxydiaminopyrimidine = phosphonylmethoxypropyldiaminopurine > tenofovir ≥ adefovir > stavudine. PMID:17470654

  15. Acyclic Lipids in Amazon Shelf Waters

    NASA Astrophysics Data System (ADS)

    Elias, V. O.; Cardoso, J. N.; Simoneit, B. R. T.

    2000-02-01

    Acyclic lipids were analysed for dissolved (<1·2 μm) and particulate (>1·2 μm) material from surface water of the Amazon continental shelf to correlate the direct inputs with diagenetic processes of the organic matter and to assess the differences in compound distribution patterns of the samples. The dissolved samples contained n -alkanes with an unusual even-to-odd carbon number predominance acyclic lipids indicates an origin from micro-organisms, probably diatoms. Although minor, a contribution of components derived from plant waxes are more abundant in the particulate phase with profiles indicating a remineralized residue. Plant waxes are effectively biodegraded in the shelf waters during downstream transport in the Amazon River. Furthermore, the Pr/Ph ratios calculated for the dissolved samples indicate that the organic matter in the surface of the highly turbid waters passed through an anaerobic stage. The differences in the acyclic hydrocarbon profiles of the dissolved and particulate phases show that organic inputs are preserved differently in smaller and larger particles.

  16. Nucleoside Inhibitors of Zika Virus.

    PubMed

    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

  17. Synthesis of novel fluorocarbocyclic nucleosides and nucleotides as potential inhibitors of human immunodeficiency virus

    SciTech Connect

    Hilpert, H.

    1989-01-01

    3[prime]-Azido-3[prime]-deoxythymidine (AZT) and 2[prime], 3[prime]-dideoxycytidine (DDC) are potent in vivo inhibitors of human immunodeficiency virus. Due to their short half-life in the body and undesired side-effects compounds with improved bioavailability were designed. A feature of these analogues was the replacement of the heterocyclic oxygen atom by an isosteric CHF-group thus stabilizing the labile glycosidic bond against metabolic breakdown. A versatile and short synthesis, starting from ketone, serves to construct the highly functionalized and protected key intermediates. These ([alpha]- and [beta]-fluoro epimeric) intermediates were elaborated to eight fluorocarbocyclic nucleoside analogues linked with a thymine base, an adenine base, and a guanine base. An attempt was made to prepare analogues of the potent HIV inhibitor carbovir c. The unexpected oxidation of the double bond of compound d, instead of the desired Baeyer-Villiger ring-expansion, meant that the synthetic scheme was redundant. A second total synthesis involves the preparation of the three fluorocarbocyclic phosphonates. These analogues possess additionally a P-C linkage which should markedly enhance the stability of the side chain. To perform enzyme inhibition tests, three analogues were chemically activated to the biologically active triphosphates. Inhibition tests on HIV associated reverse transcriptase confirmed the high activity of one of the AZT triphosphates. The fluorocarbocyclic counterpart was two orders of magnitude less active. A fluorocarbocyclic phosphonate was twice as active as the AZT triphosphate. Neither the eight nucleoside analogues nor the three phosphonates displayed significant activity against HIV infected cells. Crystallographic data of two fluorocarbocyclic nucleosides, two potent HIV inhibitors, and some 20 examples of 2[prime]-deoxyribonucleosides have been compared.

  18. Phosphonylated Acyclic Guanosine Analogues with the 1,2,3-Triazole Linker.

    PubMed

    Głowacka, Iwona E; Andrei, Graciela; Schols, Dominique; Snoeck, Robert; Piotrowska, Dorota G

    2015-01-01

    A novel series of {4-[(2-amino-6-chloro-9H-purin-9-yl)methyl]-1H-1,2,3-triazol-1-yl}alkylphosphonates and {4-[(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)methyl]-1H-1,2,3-triazol-1-yl}alkylphosphonates as acyclic analogues of guanosine were synthesized and assessed for antiviral activity against a broad range of DNA and RNA viruses and for their cytostatic activity toward three cancerous cell lines (HeLa, L1210 and CEM). They were devoid of antiviral activity; however, several phosphonates were found slightly cytostatic against HeLa cells at an IC50 in the 80-210 µM range. Compounds (1R,2S)-17k and (1S,2S)-17k showed the highest inhibitory effects (IC50=15-30 µM) against the proliferation of murine leukemia (L1210) and human T-lymphocyte (CEM) cell lines. PMID:26501246

  19. Approved Antiviral Drugs over the Past 50 Years.

    PubMed

    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

  20. Phosphonate Based High Nuclearity Magnetic Cages.

    PubMed

    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

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

    SciTech Connect

    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

  2. Peramivir Phosphonate Derivatives as Influenza Neuraminidase Inhibitors.

    PubMed

    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

  3. Microbial transformation of nucleosides

    NASA Technical Reports Server (NTRS)

    Lamba, S. S.

    1979-01-01

    A study involving the use of coulter counter in studying the effects of neomycin on E. coli, S. aureus and A. aerogenes was completed. The purpose of this was to establish proper technique for enumeration of cells per ml. It was found that inhibitory effects on growth of E. coli and A. aerogenes, both gram negative organisms, were directly related to the concentration of neomycin used. However, in case S. aureus, a gram positive organism, a decreased inhibition was noted at higher concentrations. A paper entitled, Use of Coulter Counter in Studying Effect of Drugs on Cells in Culture 1 - Effects of Neomycin on E. coli, S. aureus and A. aerogenes, is attached in the appendix. Laboratory procedures were also established to study the effects of nucleoside antibiotic cordycepin on He La cell grown in suspension cultures.

  4. [Purine nucleoside phosphorylase].

    PubMed

    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

  5. Structural basis of nucleoside and nucleoside drug selectivity by concentrative nucleoside transporters

    PubMed Central

    Johnson, Zachary Lee; Lee, Jun-Ho; Lee, Kiyoun; Lee, Minhee; Kwon, Do-Yeon; Hong, Jiyong; Lee, Seok-Yong

    2014-01-01

    Concentrative nucleoside transporters (CNTs) are responsible for cellular entry of nucleosides, which serve as precursors to nucleic acids and act as signaling molecules. CNTs also play a crucial role in the uptake of nucleoside-derived drugs, including anticancer and antiviral agents. Understanding how CNTs recognize and import their substrates could not only lead to a better understanding of nucleoside-related biological processes but also the design of nucleoside-derived drugs that can better reach their targets. Here, we present a combination of X-ray crystallographic and equilibrium-binding studies probing the molecular origins of nucleoside and nucleoside drug selectivity of a CNT from Vibrio cholerae. We then used this information in chemically modifying an anticancer drug so that it is better transported by and selective for a single human CNT subtype. This work provides proof of principle for utilizing transporter structural and functional information for the design of compounds that enter cells more efficiently and selectively. DOI: http://dx.doi.org/10.7554/eLife.03604.001 PMID:25082345

  6. Palladium-Catalyzed α-Arylation of Benzylic Phosphonates

    PubMed Central

    2015-01-01

    A new synthetic route to access diarylmethyl phosphonates is presented. The transformation enables the introduction of aromatic groups on benzylic phosphonates via a deprotonative cross-coupling process (DCCP). The Pd(OAc)2/CataCXium A-based catalyst afforded a reaction between benzyl diisopropyl phosphonate derivatives and aryl bromides in good to excellent isolated yields (64–92%). PMID:24520897

  7. 40 CFR 721.10069 - Ether amine phosphonate (generic).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Ether amine phosphonate (generic). 721... Substances § 721.10069 Ether amine phosphonate (generic). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as ether amine phosphonate (PMN...

  8. 40 CFR 721.10069 - Ether amine phosphonate (generic).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Ether amine phosphonate (generic). 721... Substances § 721.10069 Ether amine phosphonate (generic). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as ether amine phosphonate (PMN...

  9. Directed Acyclic Graphs for Oral Disease Research.

    PubMed

    Akinkugbe, A A; Sharma, S; Ohrbach, R; Slade, G D; Poole, C

    2016-07-01

    Directed acyclic graphs (DAGs) are nonparametric graphical tools used to depict causal relations in the epidemiologic assessment of exposure-outcome associations. Although their use in dental research was first advocated in 2002, DAGs have yet to be widely adopted in this field. DAGs help identify threats to causal inference such as confounders, bias due to subject selection, and inappropriate handling of missing data. DAGs can also inform the data analysis strategy based on relations among variables depicted on it. This article uses the example of a study of temporomandibular disorders (TMDs), investigating causal effects of facial injury on subsequent risk of TMD. We illustrate how DAGs can be used to identify 1) potential confounders, 2) mediators and the consequences of attempt to estimate direct causal effects, 3) colliders and the consequences of conditioning on colliders, and 4) variables that are simultaneously mediators and confounders and the consequences of adjustment for such variables. For example, one DAG shows that statistical adjustment for the pressure pain threshold would necessarily bias the causal relation between facial injury and TMD. Finally, we discuss the usefulness of DAGs during study design, subject selection, and choosing variables to be measured in a study. PMID:27000052

  10. Nucleoside transporters in the disposition and targeting of nucleoside analogs in the kidney.

    PubMed

    Mangravite, Lara M; Badagnani, Ilaria; Giacomini, Kathleen M

    2003-10-31

    Systemic disposition of nucleosides and nucleoside analogs is dependent on renal handling of these compounds. There are five known, functionally characterized nucleoside transporters with varying substrate specificities for nucleosides: concentrative nucleoside transporters (CNT1-CNT3; Solute Carrier (SLC) 28A1-28A3), which mediate the intracellular flux of nucleosides, and equilibrative nucleoside transporters (ENT1-ENT2; SLC29A1-SLC29A2), which mediate bi-directional facilitated diffusion of nucleosides. All five of these transporters are expressed in the kidney. Concentrative nucleoside transporters primarily localize to the apical membrane of renal epithelial cells while equilibrative nucleoside transporters primarily localize to the basolateral membrane. These transporters work in concert to mediate reabsorptive flux of naturally occurring nucleosides and nucleoside analogs. In addition, equilibrative transporters also participate in secretory flux of some nucleoside analogs. Nucleoside transporters also serve in the targeting of nucleoside analog therapies to renal tumors. This review examines the role that these transporters play in renal disposition of nucleosides and nucleoside analogs in both systemic and kidney-specific therapies. PMID:14612157

  11. On the acyclicity of the solution sets of operator equations

    SciTech Connect

    Gel'man, Boris D

    2010-12-07

    A parameter-dependent completely continuous map is considered. The acyclicity of the set of fixed points of this map is proved for some fixed value of the parameter under the assumption that for close values of the parameter the map has a unique fixed point. The results obtained are used to prove the acyclicity of the set of fixed points of a 'nonscattering' map, as well as to study the topological structure of the set of fixed points of an abstract Volterra map. Bibliography: 13 titles.

  12. Inhibition of adenosine kinase by phosphonate and bisphosphonate derivatives.

    PubMed

    Park, Jae; Singh, Bhag; Gupta, Radhey S

    2006-02-01

    The enzyme adenosine kinase (AK) plays a central role in regulating the intracellular and interstitial concentration of the purine nucleoside adenosine (Ado). In view of the beneficial effects of Ado in protecting tissues from ischemia and other stresses, there is much interest in developing AK inhibitors, which can regulate Ado concentration in a site- and event-specific manner. The catalytic activity of AK from different sources is dependent upon the presence of activators such as phosphate (Pi). In this work we describe several new phosphorylated compounds which either activate or inhibit AK. The compounds acetyl phosphate, carbamoyl phosphate, dihydroxyacetone phosphate and imidodiphosphate were found to stimulate AK activity in a dose-dependent manner comparable to that seen with Pi. In contrast, a number of phosphonate and bisphosphonate derivatives, which included clodronate and etidronate, were found to inhibit the activity of purified AK in the presence of Pi. These AK inhibitors (viz. clodronate, etidronate, phosphonoacetic acid, 2-carboxyethylphosphonic acid, N-(phosphonomethyl)-glycine and N-(phosphonomethyl)iminodiacetic acid), at concentrations at which they inhibited AK, were also shown to inhibit the uptake of (3)H-adenosine and its incorporation into macromolecules in cultured mammalian cells, indicating that they were also inhibiting AK in intact cells. The drug concentrations at which these effects were observed showed limited toxicity to the cultured cells, indicating that these effects are not caused by cellular toxicity. These results indicate that the enzyme AK provides an additional cellular target for the clinically widely used bisphosphonates and related compounds, which could possibly be exploited for a new therapeutic application. Our structure-activity studies on different AK activators and inhibitors also indicate that all of the AK activating compounds have a higher partial positive charge (delta(+)) on the central phosphorous atom in

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

    PubMed

    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

  14. The concentrative nucleoside transporter family, SLC28.

    PubMed

    Gray, Jennifer H; Owen, Ryan P; Giacomini, Kathleen M

    2004-02-01

    The SLC28 family consists of three subtypes of sodium-dependent, concentrative nucleoside transporters, CNT1, CNT2, and CNT3 (SLC28A1, SLC28A2, and SLC28A3, respectively), that transport both naturally occurring nucleosides and synthetic nucleoside analogs used in the treatment of various diseases. These subtypes differ in their substrate specificities: CNT1 is pyrimidine-nucleoside preferring, CNT2 is purine-nucleoside preferring, and CNT3 transports both pyrimidine and purine nucleosides. Recent studies have identified key amino acid residues that are determinants of pyrimidine and purine specificity of CNT1 and CNT2. The tissue distributions of the CNTs vary: CNT1 is localized primarily in epithelia, whereas CNT2 and CNT3 have more generalized distributions. Nucleoside transporters in the SLC28 and SLC29 families play critical roles in nucleoside salvage pathways where they mediate the first step of nucleotide biosynthesis. In addition, these transporters work in concert to terminate adenosine signaling. SLC28 family members are crucial determinants of response to a variety of anticancer and antiviral nucleoside analogs, as they modulate the entry of these analogs into target tissues. Further, this family is involved in the absorption and disposition of many nucleoside analogs. Several CNT single nucleoside polymorphisms (SNPs) have been identified, but have yet to be characterized. PMID:12856181

  15. 40 CFR 721.10067 - Ether amine phosphonate salt (generic).

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Ether amine phosphonate salt (generic... Specific Chemical Substances § 721.10067 Ether amine phosphonate salt (generic). (a) Chemical substances... ether amine phosphonate salt (PMNs P-05-57, P-05-58, P-05-59, P-05-61, P-05-62, P-05-63, P-05-64, and...

  16. 40 CFR 721.10067 - Ether amine phosphonate salt (generic).

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Ether amine phosphonate salt (generic... Specific Chemical Substances § 721.10067 Ether amine phosphonate salt (generic). (a) Chemical substances... ether amine phosphonate salt (PMNs P-05-57, P-05-58, P-05-59, P-05-61, P-05-62, P-05-63, P-05-64, and...

  17. 40 CFR 721.10067 - Ether amine phosphonate salt (generic).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Ether amine phosphonate salt (generic... Specific Chemical Substances § 721.10067 Ether amine phosphonate salt (generic). (a) Chemical substances... ether amine phosphonate salt (PMNs P-05-57, P-05-58, P-05-59, P-05-61, P-05-62, P-05-63, P-05-64, and...

  18. 40 CFR 721.10067 - Ether amine phosphonate salt (generic).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Ether amine phosphonate salt (generic... Specific Chemical Substances § 721.10067 Ether amine phosphonate salt (generic). (a) Chemical substances... ether amine phosphonate salt (PMNs P-05-57, P-05-58, P-05-59, P-05-61, P-05-62, P-05-63, P-05-64, and...

  19. 40 CFR 721.10067 - Ether amine phosphonate salt (generic).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Ether amine phosphonate salt (generic... Specific Chemical Substances § 721.10067 Ether amine phosphonate salt (generic). (a) Chemical substances... ether amine phosphonate salt (PMNs P-05-57, P-05-58, P-05-59, P-05-61, P-05-62, P-05-63, P-05-64, and...

  20. Actinide phosphonate complexes in aqueous solutions

    SciTech Connect

    Nash, K.L.

    1993-10-01

    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 (-PO{sub 3}H{sub 2}) 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.

  1. Epoxy Phosphonate Crosslinkers for Providing Flame Resistance to Cotton Textiles

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Two new monomers (2-methyl-oxiranylmethyl)-phosphonic acid dimethyl ester (3) and [2-(dimethoxy-phosphorylmethyl)-oxyranylmethyl]-phosphonic acid dimethyl ester (6) were prepared and used with dicyandiamide (7) and citric acid (8) to impart flame resistance to cotton plain weave, twill, and 80:20-co...

  2. 40 CFR 721.6070 - Alkyl phosphonate ammonium salts.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Alkyl phosphonate ammonium salts. 721... Substances § 721.6070 Alkyl phosphonate ammonium salts. (a) Chemical substances and significant new uses... salts (PMNs P-93-725 and P-93-726) are subject to reporting under this section for the significant...

  3. 40 CFR 721.6070 - Alkyl phosphonate ammonium salts.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Alkyl phosphonate ammonium salts. 721... Substances § 721.6070 Alkyl phosphonate ammonium salts. (a) Chemical substances and significant new uses... salts (PMNs P-93-725 and P-93-726) are subject to reporting under this section for the significant...

  4. 40 CFR 721.6070 - Alkyl phosphonate ammonium salts.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Alkyl phosphonate ammonium salts. 721... Substances § 721.6070 Alkyl phosphonate ammonium salts. (a) Chemical substances and significant new uses... salts (PMNs P-93-725 and P-93-726) are subject to reporting under this section for the significant...

  5. 40 CFR 721.6070 - Alkyl phosphonate ammonium salts.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Alkyl phosphonate ammonium salts. 721... Substances § 721.6070 Alkyl phosphonate ammonium salts. (a) Chemical substances and significant new uses... salts (PMNs P-93-725 and P-93-726) are subject to reporting under this section for the significant...

  6. 40 CFR 721.6070 - Alkyl phosphonate ammonium salts.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Alkyl phosphonate ammonium salts. 721... Substances § 721.6070 Alkyl phosphonate ammonium salts. (a) Chemical substances and significant new uses... salts (PMNs P-93-725 and P-93-726) are subject to reporting under this section for the significant...

  7. Diversity and abundance of phosphonate biosynthetic genes in nature

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Phosphonates, molecules containing direct C-P bonds, comprise a structurally diverse class of natural products with interesting and useful biological properties. Although their synthesis in protozoa was discovered more than fifty years ago, the extent and diversity of phosphonate production in natur...

  8. Marine Nucleosides: Structure, Bioactivity, Synthesis and Biosynthesis

    PubMed Central

    Huang, Ri-Ming; Chen, Yin-Ning; Zeng, Ziyu; Gao, Cheng-Hai; Su, Xiangdong; Peng, Yan

    2014-01-01

    Nucleosides are glycosylamines that structurally form part of nucleotide molecules, the building block of DNA and RNA. Both nucleosides and nucleotides are vital components of all living cells and involved in several key biological processes. Some of these nucleosides have been obtained from a variety of marine resources. Because of the biological importance of these compounds, this review covers 68 marine originated nucleosides and their synthetic analogs published up to June 2014. The review will focus on the structures, bioactivities, synthesis and biosynthetic processes of these compounds. PMID:25474189

  9. Base-Modified Nucleosides: Etheno Derivatives

    PubMed Central

    Jahnz-Wechmann, Zofia; Framski, Grzegorz R.; Januszczyk, Piotr A.; Boryski, Jerzy

    2016-01-01

    This review presents synthesis and chemistry of nucleoside analogs, possessing an additional fused, heterocyclic ring of the “etheno” type, such as 1,N6-ethenoadenosine, 1,N4-ethenocytidine, 1,N2-ethenoguanosine, and other related derivatives. Formation of ethenonucleosides, in the presence of α-halocarbonyl reagents and their mechanism, stability, and degradation, reactions of substitution and transglycosylation, as well as their application in the nucleoside synthesis, have been described. Some of the discussed compounds may be applied as chemotherapeutic agents in antiviral and anticancer treatment, acting as pro-nucleosides of already known, biologically active nucleoside analogs. PMID:27200341

  10. Diversity and abundance of phosphonate biosynthetic genes in nature

    PubMed Central

    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

    Phosphonates, molecules containing direct carbon–phosphorus bonds, compose a structurally diverse class of natural products with interesting and useful biological properties. Although their synthesis in protozoa was discovered more than 50 y ago, the extent and diversity of phosphonate production in nature remains poorly characterized. The rearrangement of phosphoenolpyruvate (PEP) to phosphonopyruvate, catalyzed by the enzyme PEP mutase (PepM), is shared by the vast majority of known phosphonate biosynthetic pathways. Thus, the pepM gene can be used as a molecular marker to examine the occurrence and abundance of phosphonate-producing organisms. Based on the presence of this gene, phosphonate biosynthesis is common in microbes, with ∼5% of sequenced bacterial genomes and 7% of genome equivalents in metagenomic datasets carrying pepM homologs. Similarly, we detected the pepM gene in ∼5% of random actinomycete isolates. The pepM-containing gene neighborhoods from 25 of these isolates were cloned, sequenced, and compared with those found in sequenced genomes. PEP mutase sequence conservation is strongly correlated with conservation of other nearby genes, suggesting that the diversity of phosphonate biosynthetic pathways can be predicted by examining PEP mutase diversity. We used this approach to estimate the range of phosphonate biosynthetic pathways in nature, revealing dozens of discrete groups in pepM amplicons from local soils, whereas hundreds were observed in metagenomic datasets. Collectively, our analyses show that phosphonate biosynthesis is both diverse and relatively common in nature, suggesting that the role of phosphonate molecules in the biosphere may be more important than is often recognized. PMID:24297932

  11. Alkyl phosphonic acids and sulfonic acids in the Murchison meteorite

    NASA Technical Reports Server (NTRS)

    Cooper, George W.; Onwo, Wilfred M.; Cronin, John R.

    1992-01-01

    Homologous series of alkyl phosphonic acids and alkyl sulfonic acids, along with inorganic orthophosphate and sulfate, are identified in water extracts of the Murchison meteorite after conversion to their t-butyl dimethylsilyl derivatives. The methyl, ethyl, propyl, and butyl compounds are observed in both series. Five of the eight possible alkyl phosphonic acids and seven of the eight possible alkyl sulfonic acids through C4 are identified. Abundances decrease with increasing carbon number as observed of other homologous series indigenous to Murchison. Concentrations range downward from approximately 380 nmol/gram in the alkyl sulfonic acid series, and from 9 nmol/gram in the alkyl phosphonic acid series.

  12. Design, Synthesis, and Evaluation of Anti-HBV Activity of Hybrid Molecules of Entecavir and Adefovir: Exomethylene Acycloguanine Nucleosides and Their Monophosphate Derivatives.

    PubMed

    Imoto, Shuhei; Kohgo, Satoru; Tokuda, Ryoh; Kumamoto, Hiroki; Aoki, Manabu; Amano, Masayuki; Kuwata-Higashi, Nobuyo; Mitsuya, Hiroaki; Haraguchi, Kazuhiro

    2015-01-01

    Exomethylene acycloguanine nucleosides 4, 6 and its monophosphate derivatives 5, 7, and 8 have been synthesized. Mitsunobu-type coupling of 2-N-acetyl-6-O-diphenylcarbamoylguanine (11) with primary alcohols proceeded regioselectively to furnish the desired N(9)-substituted products in moderate yield. Evaluation of 4-8 for anti-HBV activity in HepG2 cells revealed that the phosphonate derivative 8 was found to exhibit moderated activity (EC50 value of 0.29 μM), but cytotoxicity (CC50 value of 39 μM) against the host cells was also observed. PMID:26167667

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

    PubMed

    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. PMID:25625304

  14. Developmental Toxicity of Perfluorinated Phosphonic Acids in Mice

    EPA Science Inventory

    Perfluorinated phosphonic acids (PFPAs) are a third member of the perfluoroalkyl acid (PFAA) family, and are structurally similar to the perfluoroalkyl sulfonates and perfluoroalkyl carboxylates. PFPAs are used primarily as a surfactant defoaming agent in pesticide production. Re...

  15. Polymorphic Lanthanide Phosphonates Showing Distinct Magnetic Behavior.

    PubMed

    Zeng, Dai; Ren, Min; Bao, Song-Song; Cai, Zhong-Sheng; Xu, Chang; Zheng, Li-Min

    2016-06-01

    A series of layered lanthanide phosphonates α-Ln(2-qpH)(SO4)(H2O)2 (α-Ln; Ln = Gd, Tb, Ho, Er) and β-Ln(2-qpH)(SO4)(H2O)2 (β-Ln; Ln = Gd, Tb, Ho, Er, Yb) (2-qpH2 = 2-quinolinephosphonic acid) have been synthesized and characterized. Compounds α-Ln crystallize in monoclinic space group P21/c, while compounds β-Ln crystallize in triclinic space group P1̅. Magnetic studies reveal that dominant ferromagnetic interactions are propagated between the magnetic centers in all cases. Field-induced magnetic relaxation is observed in compounds β-Er and β-Yb. PMID:27183034

  16. Betulin Phosphonates; Synthesis, Structure, and Cytotoxic Activity.

    PubMed

    Chrobak, Elwira; Bębenek, Ewa; Kadela-Tomanek, Monika; Latocha, Małgorzata; Jelsch, Christian; Wenger, Emmanuel; Boryczka, Stanisław

    2016-01-01

    Betulin derivatives are a widely studied group of compounds of natural origin due to their wide spectrum of biological activities. This paper describes new betulin derivatives, containing a phosphonate group. The allyl-vinyl isomerization and synthesis of acetylenic derivatives have been reported. Structural identification of products as E and Z isomers has been carried out using ¹H-, (13)C-, (31)P-NMR, and crystallographic analysis. The crystal structure in the orthorhombic space group and analysis of crystal packing contacts for 29-diethoxyphosphoryl-28-cyclopropylpropynoyloxy-lup-20E(29)-en-3β-ol 8a are reported. All new compounds were tested in vitro for their antiproliferative activity against human T47D (breast cancer), SNB-19 (glioblastoma), and C32 (melanoma) cell lines. PMID:27571057

  17. Synthesis of phosphonate and phostone analogues of ribose-1-phosphates

    PubMed Central

    Nasomjai, Pitak; Slawin, Alexandra M Z

    2009-01-01

    Summary The synthesis of phosphonate analogues of ribose-1-phosphate and 5-fluoro-5-deoxyribose-1-phosphate is described. Preparations of both the α- and β-phosphonate anomers are reported for the ribose and 5-fluoro-5-deoxyribose series and a synthesis of the corresponding cyclic phostones of each α-ribose is also reported. These compounds have been prepared as tools to probe the details of fluorometabolism in S. cattleya. PMID:19777136

  18. Reactivity of vinyl phosphonate containing diazoesters: formation, reactivity, and utility.

    PubMed

    Wang, Jin; Rainier, Jon D

    2015-01-16

    Treatment of diazo vinyl phosphonate with alcohols, amines, and thiols in the presence of Rh(II) results in the chemo- and stereoselective generation of enol ethers, enamines and vinyl sulfides via an X-H insertion process. The utility of the products from these reactions was demonstrated through their conversion into quaternary substituted heterocycles including furans and oxetanes as highlighted by the generation of a bicyclic phosphonate analogue of neodysiherbaine. PMID:25534147

  19. Structural modifications of nucleosides in ionic liquids

    PubMed Central

    Kumar, Vineet; Parmar, Virinder S.; Malhotra, Sanjay V.

    2011-01-01

    Nucleoside chemistry represents an important research area for drug discovery, as many nucleoside analogs are prominent drugs and have been widely applied for cancer and viral chemotherapy. However, the synthesis of modified nucleosides presents a major challenge, which is further aggravated by poor solubility of these compounds in common organic solvents. Most of the currently available methods for nucleoside modification employ toxic high boiling solvents; require long reaction time and tedious workup methods. As such, there is constant effort to develop process chemistry in alternative medium to limit the use of organic solvents that are hazardous to the environment and can be deleterious to human health. One such approach is to use ionic liquids, which are ‘designer materials’ with unique and tunable physico-chemical properties. Studies have shown that methodologies using ionic liquids are highly efficient and convenient for the synthesis of nucleoside analogs, as demonstrated by the preparation of pharmaceutically important anti-viral drugs. This article summarizes recent efforts on nucleoside modification using ionic liquids. PMID:20178825

  20. Synthesis and characterization of phosphonate ester and phosphonic acid containing polymers and blends

    NASA Astrophysics Data System (ADS)

    Tamber, Harinder Singh

    1997-12-01

    Vinylbenzylphosphonate ester (VBP) was homopolymerized and copolymerized with methyl methacrylate and the reactivity ratio of this pair of monomers was calculated from Finneman-Ross and Kelen-Tudos methods. These methods provided identical values, which are rsb1 (VBP) = 1.23 and rsb2(MMA) = 0.43. The phosphonate ester group, -P = O(OEt)sb2; in VBP and poly(VBP-MMA) copolymers was hydrolysed to phosphonic acid, -P = O(OH)sb2; at room temperature to obtain vinylbenzylphosphonic acid (VBPa) and poly(VBPa-MMA) copolymers. sp1H, sp{13}C & sp{31}P NMR spectroscopy, DSC and FTIR were used to monitor the hydrolysis of these phosphorylated monomers and polymers. The glass transition temperature of PVBP was 13sp°C as compared to 198sp°C of PVBPa. The phosphoryl group in the parent polymers acts as a self plasticizing agent resulting in lower glass transition temperature, on the other hand inter and intra hydrogen bonding results in broad and high Tsbg in these hydrolysed polymers. VBP was also polymerized with BisGMA or TEGDM to low conversions. These oligomers were tested in vitro as potential adhesive materials for dental/enamel and composite resins. The phosphonate esters containing polymers show substantial capacity to dissolve the heavy metal salts, e.g., UOsb2(NO)sb3.6Hsb2O and thus provides radiopaque polymers. Excessive sorption of water lead to phase separation and, hence, loss of radiopacity. Thus, an alternate method of synthesis of radiopaque polymers is also described in which radiopacifying agent is covalently linked to polymer backbone. Styryldiphenylbismuth was prepared by the reaction of diphenylbismuthchloride and Grignard of p-bromostyrene, but some other by-products such as triphenylbismuth, distyrylphenyl bismoth were also obtained as revealed by reverse phase HPLC and the yield of the reaction was low. Iodinated monomers VBTIsb3 and IEMIsb3 were prepared by reacting VBC or IEM to triiodophenol in high yields. Decomposition kinetic analysis was done by

  1. Iridium-Catalyzed Diastereoselective and Enantioselective Allylic Substitutions with Acyclic α-Alkoxy Ketones.

    PubMed

    Jiang, Xingyu; Chen, Wenyong; Hartwig, John F

    2016-05-01

    The asymmetric alkylation of acyclic ketones is a longstanding challenge in organic synthesis. Reported herein are diastereoselective and enantioselective allylic substitutions with acyclic α-alkoxy ketones catalyzed by a metallacyclic iridium complex to form products with contiguous stereogenic centers derived from the nucleophile and electrophile. These reactions occur between allyl methyl carbonates and unstabilized copper(I) enolates generated in situ from acyclic α-alkoxy ketones. The resulting products can be readily converted into enantioenriched tertiary alcohols and tetrahydrofuran derivatives without erosion of enantiomeric purity. PMID:27038004

  2. Forming Stereogenic Centers in Acyclic Systems from Alkynes.

    PubMed

    Vabre, Roxane; Island, Biana; Diehl, Claudia J; Schreiner, Peter R; Marek, Ilan

    2015-08-17

    The combined carbometalation/zinc homologation followed by reactions with α-heterosubstituted aldehydes and imines proceed through a chair-like transition structure with the substituent of the incoming aldehyde residue preferentially occupying a pseudo-axial position to avoid the two gauche interactions. The heteroatom in the axial position produces a chelated intermediate (and not a Cornforth-Evans transition structure for α-chloro aldehydes and imines) leading to a face differentiation in the allylation reaction. This method provides access to functionalized products in which three new carbon-carbon bonds and two to three stereogenic centers, including a quaternary one, were created in acyclic systems in a single-pot operation from simple alkynes. PMID:26130570

  3. Tautomerism and stereodynamics of acyclic. beta. -diketo esters

    SciTech Connect

    Romas, A.D.; Esakov, S.M.; Petrov, Al.An.; Ershov, B.A.

    1986-04-10

    The tautomeric transformations and stereodynamics of a series of ring-substituted acyclic ..beta..-diketo esters p-XC/sub 6/H/sub 4/COCH(CH/sub 3/CO)CO/sub 2/CH/sub 3/ in hexachlorobutadiene and nitrobenzene were investigated by proton and carbon magnetic resonance spectroscopy. The enolization of the compounds is accompanied by the formation of two cis-enol forms (of the three theoretically possible forms) with nonchelated benzene of methoxycarbonyl groups respectively. The form with the nonchelated methoxycarbonyl group predominates in the equilibrium on account of the smaller loss of entropy during its formation compared with the enol containing the nonchelated benzoyl group. The kinetic characteristics of the mutual transformations of the enolic forms in hexachlorobutadiene and nitrobenzene respectively were determined by integration and dynamic nuclear magnetic resonance.

  4. Analyzing microarray data with transitive directed acyclic graphs.

    PubMed

    Phan, Vinhthuy; Olusegun George, E; Tran, Quynh T; Goodwin, Shirlean; Bodreddigari, Sridevi; Sutter, Thomas R

    2009-02-01

    Post hoc assignment of patterns determined by all pairwise comparisons in microarray experiments with multiple treatments has been proven to be useful in assessing treatment effects. We propose the usage of transitive directed acyclic graphs (tDAG) as the representation of these patterns and show that such representation can be useful in clustering treatment effects, annotating existing clustering methods, and analyzing sample sizes. Advantages of this approach include: (1) unique and descriptive meaning of each cluster in terms of how genes respond to all pairs of treatments; (2) insensitivity of the observed patterns to the number of genes analyzed; and (3) a combinatorial perspective to address the sample size problem by observing the rate of contractible tDAG as the number of replicates increases. The advantages and overall utility of the method in elaborating drug structure activity relationships are exemplified in a controlled study with real and simulated data. PMID:19226664

  5. Synthesis and biological evaluation of a phosphonate analog of the natural acetyl cholinesterase inhibitor cyclophostin.

    PubMed

    Bandyopadhyay, Saibal; Dutta, Supratik; Spilling, Christopher D; Dupureur, Cynthia M; Rath, Nigam P

    2008-11-01

    Two diastereomers of a phosphonate analog 6 of the AChE inhibitor cyclophostin were synthesized. The substitution reaction of phosphono allylic carbonate 10a with methyl acetoacetate gave the vinyl phosphonate 9a. Attempted hydrogenation/debenzylation gave an unexpected enolether lactone. Alternatively, selective hydrogenation, demethylation, cyclization and debenzylation gave the phosphonate analog of cyclophostin as a separable mixture of diastereomers 6. The trans phosphonate isomer was more active than the cis isomer against AChE from two sources. PMID:18821801

  6. Interaction of potassium phosphonate fungicide in laterite soil.

    PubMed

    Kumar, R Anil; Velayudhan, K T; Vasu, K; Ramachandran, V; Bhai, R Susheela; Unnikrishnan, G

    2005-10-01

    Potassium phosphonate is a fungicide widely used to control Phytophthora fungi species in many crops all over the world. In this paper, an attempt has been made to study the interaction of potassium phosphonate with soil under varying pH and calcium level. Several reports available in literature indicate that the phosphonate in organic form adsorb strongly on almost all mineral surfaces and natural materials like soil and sediments. The present study conducted on laterite soil of Kerala using 2 mm sieved sample indicated that phosphonate obeys Freundlich adsorption isotherm. Though at lower concentrations, Langmuir model equally fits well, deviation was observed at higher concentrations. pH and calcium content of the soil had striking influence on the interaction of the chemical with the soil. The calcium source also appeared to influence the adsorption phenomenon. Since potassium phosphonate is extensively used to control Phytophthora fungi species in black pepper (Piper nigrum) plantations in India and liming is a standard practice followed as soil amendment in acid soils to increase the soil pH, this study may help to maintain good soil quality. PMID:17051913

  7. Structural characterization and electrochemical properties of novel salicylidene phosphonate derivatives

    NASA Astrophysics Data System (ADS)

    Dolaz, Mustafa; McKee, Vickie; Köse, Muhammet; Gölcü, Ayşegül; Tümer, Mehmet

    2010-09-01

    In this study, three novel salicylidene phosphonate ligands, diethyl (4-{[(1 E)-(2-hydroxyphenyl)methylidene]amino}benzyl)phosphonate (HL 1), diethyl (4-{[(1 E)-(2-hydroxy-3-methoxyphenyl)methylidene]amino}benzyl)phosphonate (HL 2) and diethyl (4-{[(1 E)-(2,4-dihydroxyphenyl)methylidene]amino}benzyl)phosphonate (HL 3) were synthesized and characterized by the analytical and spectroscopic techniques. We obtained their single crystals from the ethanolic solution. There are intramolecular phenol-imine hydrogen bonds in all three compounds between O1 and N1 atoms. The ligand HL 3 contains a second phenol group and this is makes an intermolecular hydrogen bond with the phosphine oxide of a neighbouring molecule O2-O3 (under symmetry operation - x, 0.5 + y, 0.5 - z). In order to investigate the redox behaviours of the salicylidene phosphonate ligands (HL 1-HL 3), we were studied electrochemical properties of the ligands at the different pH and scan rates.

  8. Nucleoside transporters and liver cell growth.

    PubMed

    Pastor-Anglada, M; Felipe, A; Casado, F J; del Santo, B; Mata, J F; Valdés, R

    1998-01-01

    Liver parenchymal cells show a wide variety of plasma membrane transporters that are tightly regulated by endocrine and nutritional factors. This review summarizes work performed in our laboratory on these transport systems, particularly nucleoside transporters, which are up-regulated in physiological situations associated with liver cell growth. Rat hepatocytes show a Na+-dependent nucleoside transport activity that is stimulated by pancreatic hormones. Indeed, this biological activity appears to be the result of the co-expression of at least two isoforms of nucleoside carriers, CNT1 and CNT2 (also called SPNT). These two transporters are up-regulated during the early phase of liver growth after partial hepatectomy, although to different extents, suggesting differential regulation of the two isoforms. The recent generation of isoform-specific antibodies allowed us to demonstrate that carrier expression may also have complex post-transcriptional regulation on the basis of the lack of correspondence between mRNA and protein levels. The analysis of nucleoside transport systems in hepatoma cells and the comparison with those in hepatocytes has also provided evidence that the differentiation status of liver parenchymal cells may determine the pattern of nucleoside transporters expressed. PMID:10353710

  9. Prebiotic phosphorylation of nucleosides in formamide

    NASA Technical Reports Server (NTRS)

    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.

  10. Polymeric nanogel formulations of nucleoside analogs

    PubMed Central

    Vinogradov, Serguei V

    2008-01-01

    Nanogels are colloidal microgel carriers that have been introduced recently as a prospective drug delivery system for nucleotide therapeutics. The crosslinked protonated polymer network of nanogels binds oppositely charged drug molecules, encapsulating them into submicron particles with a core-shell structure. The nanogel network also provides a suitable template for chemical engineering, surface modification and vectorisation. This review reveals recent attempts to develop novel drug formulations of nanogels with antiviral and antiproliferative nucleoside analogs in the active form of 5′-triphosphates; discusses structural approaches to the optimisation of nanogel properties, and; discusses the development of targeted nanogel drug formulations for systemic administration. Notably, nanogels can improve the CNS penetration of nucleoside analogs that are otherwise restricted from passing across the blood–brain barrier. The latest findings reviewed here demonstrate an efficient intracellular release of nucleoside analogs, encouraging further applications of nanogel carriers for targeted drug delivery. PMID:17184158

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

    PubMed

    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. PMID:17275268

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

    PubMed

    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

  13. Ab initio investigation of the molecular structure of methyl methoxymethyl phosphonate, a promising nuclease-resistant alternative of the phosphodiester linkage.

    PubMed

    Strajbl, M; Florian, J

    1996-02-01

    Conformational flexibility of the methyl methoxymethyl phosphonate anion (CH3-O-PO2-CH2-O-CH3)-, a nuclease resistant alternative to the phosphodiester linkage in DNA, have been investigated by ab initio quantum mechanical calculations. The potential of backbone torsional degrees of freedom of methyl methoxymethyl phosphonate anion (MMP) was determined at the Hartree-Fock (HF) 3-21G* level using the adiabatic mapping technique. Energies, geometries, and effective atomic charges of different conformers were calculated at HF/6-31G* and MP2/6-31G* levels of theory. These were compared to the results obtained for dimethyl phosphate calculated at the same level. The impact on DNA structure from inserting a methylene group between phosphorus and oxygen of the nucleoside sugar moiety was examined via distance and angle-constrained geometry optimizations. Due to its high flexibility, MMP has been shown to be compatible with both A and B forms of DNA. PMID:8906889

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

    SciTech Connect

    Afroz, Taliman; Seo, D. M.; Han, Sang D.; Boyle, Paul D.; Henderson, Wesley A.

    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.

  15. Basolateral Uptake of Nucleosides by Sertoli Cells Is Mediated Primarily by Equilibrative Nucleoside Transporter 1

    PubMed Central

    Klein, David M.; Evans, Kristen K.; Hardwick, Rhiannon N.; Dantzler, William H.; Wright, Stephen H.

    2013-01-01

    The blood-testis barrier (BTB) prevents the entry of many xenobiotic compounds into seminiferous tubules thereby protecting developing germ cells. Understanding drug transport across the BTB may improve drug delivery into the testis. Members of one class of drug, nucleoside reverse transcriptase inhibitors (NRTIs), do penetrate the BTB, presumably through interaction with physiologic nucleoside transporters. By investigating the mechanism of nucleoside transport, it may be possible to design other drugs to bypass the BTB in a similar manner. We present a novel ex vivo technique to study transport at the BTB that employs isolated, intact seminiferous tubules. Using this system, we found that over 80% of total uptake by seminiferous tubules of the model nucleoside uridine could be inhibited by 100 nM nitrobenzylmercaptopurine riboside (NBMPR, 6-S-[(4-nitrophenyl)methyl]-6-thioinosine), a concentration that selectively inhibits equilibrative nucleoside transporter 1 (ENT1) activity. In primary cultured rat Sertoli cells, 100 nM NBMPR inhibited all transepithelial transport and basolateral uptake of uridine. Immunohistochemical staining showed ENT1 to be located on the basolateral membrane of human and rat Sertoli cells, whereas ENT2 was located on the apical membrane of Sertoli cells. Transepithelial transport of uridine by rat Sertoli cells was partially inhibited by the NRTIs zidovudine, didanosine, and tenofovir disoproxil fumarate, consistent with an interaction between these drugs and ENT transporters. These data indicate that ENT1 is the primary route for basolateral nucleoside uptake into Sertoli cells and a possible mechanism for nucleosides and nucleoside-based drugs to undergo transepithelial transport. PMID:23639800

  16. Synthesis of biologically active phosphonates from Lesquerella oil

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  18. Synthesis of glycophostones: cyclic phosphonate analogues of biologically relevant sugars

    PubMed

    Hanessian; Rogel

    2000-05-01

    Analogues of L-fucose, N-acetyl-D-glucosamine, N-acetyl-D-mannosamine, and N-acetyl neuraminic acid in which the anomeric carbon atom was replaced by a phosphonyl group (phostones or cyclic phosphonates) were synthesized by stereocontrolled methods relying on the Abramov reaction. PMID:10808439

  19. New hypoxanthine nucleosides with RNA antiviral activity.

    PubMed

    Nair, V; Ussery, M A

    1992-08-01

    A series of novel C-2 functionalized hypoxanthine and purine ribonucleosides have been synthesized and evaluated against exotic RNA viruses of the family or genus alpha, arena, flavi, and rhabdo. Both specific and broad-spectrum antiviral activities were discovered but only with hypoxanthine nucleosides. PMID:1444325

  20. Mycoplasmas and cancer: focus on nucleoside metabolism

    PubMed Central

    Vande Voorde, Johan; Balzarini, Jan; Liekens, Sandra

    2014-01-01

    The standard of care for patients suffering cancer often includes treatment with nucleoside analogues (NAs). NAs are internalized by cell-specific nucleobase/nucleoside transporters and, after enzymatic activation (often one or more phosphorylation steps), interfere with cellular nucleo(s)(t)ide metabolism and DNA/RNA synthesis. Therefore, their efficacy is highly dependent on the expression and activity of nucleo(s)(t)ide-metabolizing enzymes, and alterations thereof (e.g. by down/upregulated expression or mutations) may change the susceptibility to NA-based therapy and/or confer drug resistance. Apart from host cell factors, several other variables including microbial presence may determine the metabolome (i.e. metabolite concentrations) of human tissues. Studying the diversity of microorganisms that are associated with the human body has already provided new insights in several diseases (e.g. diabetes and inflammatory bowel disease) and the metabolic exchange between tissues and their specific microbiota was found to affect the bioavailability and toxicity of certain anticancer drugs, including NAs. Several studies report a preferential colonization of tumor tissues with some mycoplasma species (mostly Mycoplasma hyorhinis). These prokaryotes are also a common source of cell culture contamination and alter the cytostatic activity of some NAs in vitro due to the expression of nucleoside-catabolizing enzymes. Mycoplasma infection may therefore bias experimental work with NAs, and their presence in the tumor microenvironment could be of significance when optimizing nucleoside-based cancer treatment. PMID:26417262

  1. Nucleoside phosphorylation by the mineral schreibersite

    PubMed Central

    Gull, Maheen; Mojica, Mike A.; Fernández, Facundo M.; Gaul, David A.; Orlando, Thomas M.; Liotta, Charles L.; Pasek, Matthew A.

    2015-01-01

    Phosphorylation of the nucleosides adenosine and uridine by the simple mixing and mild heating of aqueous solutions of the organic compounds with synthetic analogs of the meteoritic mineral schreibersite, (Fe,Ni)3P under slightly basic conditions (pH ~9) is reported. These results suggest a potential role for meteoritic phosphorus in the origin and development of early life. PMID:26606901

  2. Characterization of nucleoside transport systems in cultured rat epididymal epithelium.

    PubMed

    Leung, G P; Ward, J L; Wong, P Y; Tse, C M

    2001-05-01

    The nucleoside transport systems in cultured epididymal epithelium were characterized and found to be similar between the proximal (caput and corpus) and distal (cauda) regions of the epididymis. Functional studies revealed that 70% of the total nucleoside uptake was Na(+) dependent, while 30% was Na(+) independent. The Na(+)-independent nucleoside transport was mediated by both the equilibrative nitrobenzylthioinosine (NBMPR)-sensitive system (40%) and the NBMPR-insensitive system (60%), which was supported by a biphasic dose response to NBMPR inhibition. The Na(+)-dependent [(3)H]uridine uptake was selectively inhibited 80% by purine nucleosides, indicating that the purine nucleoside-selective N1 system is predominant. Since Na(+)-dependent [(3)H]guanosine uptake was inhibited by thymidine by 20% and Na(+)-dependent [(3)H]thymidine uptake was broadly inhibited by purine and pyrimidine nucleosides, this suggested the presence of the broadly selective N3 system accounting for 20% of Na(+)-dependent nucleoside uptake. Results of RT-PCR confirmed the presence of mRNA for equilibrative nucleoside transporter (ENT) 1, ENT2, and concentrative nucleoside transporter (CNT) 2 and the absence of CNT1. It is suggested that the nucleoside transporters in epididymis may be important for sperm maturation by regulating the extracellular concentration of adenosine in epididymal plasma. PMID:11287319

  3. Pan-Pathway Based Interaction Profiling of FDA-Approved Nucleoside and Nucleobase Analogs with Enzymes of the Human Nucleotide Metabolism

    PubMed Central

    Egeblad, Louise; Welin, Martin; Flodin, Susanne; Gräslund, Susanne; Wang, Liya; Balzarini, Jan; Eriksson, Staffan; Nordlund, Pär

    2012-01-01

    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 ΔTagg 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. PMID:22662200

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

    NASA Astrophysics Data System (ADS)

    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.

  5. Structure of the Escherichia coli Phosphonate Binding Protein PhnD and Rationally Optimized Phosphonate Biosensors

    SciTech Connect

    Alicea, Ismael; Marvin, Jonathan S.; Miklos, Aleksandr E.; Ellington, Andrew D.; Looger, Loren L.; Schreiter, Eric R.

    2012-09-17

    The phnD gene of Escherichia coli encodes the periplasmic binding protein of the phosphonate (Pn) uptake and utilization pathway. We have crystallized and determined structures of E. coli PhnD (EcPhnD) in the absence of ligand and in complex with the environmentally abundant 2-aminoethylphosphonate (2AEP). Similar to other bacterial periplasmic binding proteins, 2AEP binds near the center of mass of EcPhnD in a cleft formed between two lobes. Comparison of the open, unliganded structure with the closed 2AEP-bound structure shows that the two lobes pivot around a hinge by {approx}70{sup o} between the two states. Extensive hydrogen bonding and electrostatic interactions stabilize 2AEP, which binds to EcPhnD with low nanomolar affinity. These structures provide insight into Pn uptake by bacteria and facilitated the rational design of high signal-to-noise Pn biosensors based on both coupled small-molecule dyes and autocatalytic fluorescent proteins.

  6. Direct phosphonation of quinoxalin-2(1H)-ones under transition-metal-free conditions.

    PubMed

    Gao, Ming; Li, Yi; Xie, Lijuan; Chauvin, Remi; Cui, Xiuling

    2016-02-01

    A direct C-H bond phosphonation of quinoxalin-2(1H)-ones with H-phosphonates, H-phosphinates or H-phosphine oxides has been developed. A wide variety of heteroaryl phosphonates were obtained in up to 92% yield for 20 examples under transition-metal-free conditions. This protocol tolerates a broad scope of substrates and features practicality, high efficiency, environmental friendliness and atom economy. PMID:26779573

  7. Rhodium-catalyzed asymmetric hydrogenation of unprotected β-enamine phosphonates.

    PubMed

    Zhou, Ming; Xue, Zejian; Cao, Min; Dong, Xiu-Qin; Zhang, Xumu

    2016-05-18

    We have successfully developed a strategy for the first time for the enantioselective Rh-TaniaPhos catalyzed asymmetric hydrogenation of unprotected β-enamine phosphonates to free β-amino phosphonates directly with good enantioselectivities (80%-86% ee) and high conversions (>99% conversion). The resulting chiral free β-amino phosphonates and their derivatives are important intermediates in biochemistry and pharmaceuticals. PMID:27137841

  8. Layered zirconium phosphonate with inorganic–organic hybrid structure: Preparation and its assembly with DNA

    SciTech Connect

    Liu, Li-Min; Lu, Guo-Yuan; Jiang, Li-Ping; Zhu, Jun-Jie

    2014-07-01

    An aminoethoxy-functionalized zirconium phosphonate (Zr(O{sub 3}POCH{sub 2}CH{sub 2}NH{sub 2}){sub 2}·3H{sub 2}O), abbreviated as ZrRP (R=OCH{sub 2}CH{sub 2}NH{sub 2}), with layered structure has been synthesized. This layered compound possesses the characteristic of inorganic–organic hybrid, due to the covalently linked aminoethoxy in the host layer. The anion exchanged property of this zirconium phosphonate is suitable for the direct intercalation of negatively charged DNA, which is different from these reported zirconium phosphates or zirconium phosphonates. As a precursor, this prepared zirconium phosphonate was utilized to fabricate a novel DNA/ZrRP binary hybrid via a delamination-reassembly procedure. The release behavior of DNA from the DNA/ZrRP composite was investigated at different medium pH, because the combination between zirconium phosphonate sheets and DNA was pH-dependent sensitively. Moreover, the helical conformation of DNA was almost retained after the intercalation and release process. These properties of the DNA/ZrRP composite suggested the potential application of layered zirconium phosphonate as a non-viral vector in gene delivery. - Graphical abstract: The intercalation of DNA into zirconium phosphonate and the release of DNA from the interlayer of zirconium phosphonate. - Highlights: ●A layered aminoethoxy-functionalized zirconium phosphonate has been synthesized. ●DNA was intercalated directly into the prepared zirconium phosphonate. ●A novel zirconium phosphonate/DNA binary hybrid was fabricated. ●DNA can be reversibly released from the interlayer of zirconium phosphonate. ●The intercalation/release processes do not induce the denaturalization of DNA.

  9. Summary: the modified nucleosides of RNA.

    PubMed Central

    Limbach, P A; Crain, P F; McCloskey, J A

    1994-01-01

    A comprehensive listing is made of posttranscriptionally modified nucleosides from RNA reported in the literature through mid-1994. Included are chemical structures, common names, symbols, Chemical Abstracts registry numbers (for ribonucleoside and corresponding base), Chemical Abstracts Index Name, phylogenetic sources, and initial literature citations for structural characterization or occurrence, and for chemical synthesis. The listing is categorized by type of RNA: tRNA, rRNA, mRNA, snRNA, and other RNAs. A total of 93 different modified nucleosides have been reported in RNA, with the largest number and greatest structural diversity in tRNA, 79; and 28 in rRNA, 12 in mRNA, 11 in snRNA and 3 in other small RNAs. PMID:7518580

  10. 2'-modified nucleosides for site-specific labeling of oligonucleotides

    NASA Technical Reports Server (NTRS)

    Krider, Elizabeth S.; Miller, Jeremiah E.; Meade, Thomas J.

    2002-01-01

    We report the synthesis of 2'-modified nucleosides designed specifically for incorporating labels into oligonucleotides. Conversion of these nucleosides to phosphoramidite and solid support-bound derivatives proceeds in good yield. Large-scale synthesis of 11-mer oligonucleotides possessing the 2'-modified nucleosides is achieved using these derivatives. Thermal denaturation studies indicate that the presence of 2'-modified nucleosides in 11-mer duplexes has minimal destabilizing effects on the duplex structure when the nucleosides are placed at the duplex termini. The powerful combination of phosphoramidite and support-bound derivatives of 2'-modified nucleosides affords the large-scale preparation of an entirely new class of oligonucleotides. The ability to synthesize oligonucleotides containing label attachment sites at 3', intervening, and 5' locations of a duplex is a significant advance in the development of oligonucleotide conjugates.

  11. Stereodefined acyclic trisubstituted metal enolates towards the asymmetric formation of quaternary carbon stereocentres.

    PubMed

    Minko, Yury; Marek, Ilan

    2014-10-28

    Reactions that involve metal enolate species are amongst the most versatile carbon-carbon bond forming processes available to synthetic chemists. Enolate species are involved in a multitude of powerful applications in asymmetric organic synthesis, but the generation of fully substituted enolates in a geometrically defined form is not easily achieved especially in acyclic systems. In this Feature Article we focus on the most prominent examples reported in the literature describing the formation of highly diastereo- and enantiomerically enriched quaternary stereocentres in acyclic molecules derived from stereodefined non-cyclic trisubstituted metal enolates. PMID:25054432

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

    PubMed

    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

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

    PubMed Central

    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

  14. Synthesis of a Series of γ-Keto Allyl Phosphonates.

    PubMed

    Elleuch, Haitham; Ayadi, Marwa; Bouajila, Jalloul; Rezgui, Farhat

    2016-03-01

    Under solvent-free conditions and at 80 °C, a DMAP- or imidazole-mediated clean and rapid conversion of cyclic Morita-Baylis-Hillman (MBH) acetates into the corresponding γ-keto allyl phosphonates in 70-93% yields is described herein. This allylic nucleophilic substitution works well with primary and secondary acetates bearing, at the β'-position, linear or branched alkyl groups and aryl groups. PMID:26872500

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

    PubMed Central

    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

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

    PubMed

    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

  17. Phosphonic Acid-Functionalized Polyurethane Dispersions with Improved Adhesion Properties.

    PubMed

    Breucker, Laura; Landfester, Katharina; Taden, Andreas

    2015-11-11

    A facile route to phosphorus-functionalized polyurethane dispersions (P-PUDs) with improved adhesion properties is presented. (Bis)phosphonic acid moieties serve as adhesion promoting sites that are covalently attached via an end-capping reaction to isocyanate-reactive polyurethane particles under aqueous conditions. The synthetic approach circumvents solubility issues, offers great flexibility in terms of polyurethane composition, and allows for the synthesis of semicrystalline systems with thermomechanical response due to reversible physical cross-linking. Differential scanning calorimetry (DSC) is used to investigate the effect of functionalization on the semicrystallinity. The end-capping conversion was determined via inductively-coupled plasma optical emission spectroscopy (ICP-OES) and was surprisingly found to be almost independent of the stoichiometry of reaction, suggesting an adsorption-dominated process. Particle charge detection (PCD) experiments reveal that a dense surface coverage of phosphonic acid groups can be attained and that, at high functionalization degrees, the phosphonic adhesion moieties are partially dragged inside the colloidal P-PUD particle. Quartz crystal microbalance with dissipation (QCMD) investigations conducted with hydroxyapatite (HAP) and stainless steel sensors as model surfaces show a greatly enhanced affinity of the aqueous P-PUDs and furthermore indicate polymer chain rearrangements and autonomous film formation under wet conditions. Due to their facile synthesis, significantly improved adhesion, and variable film properties, P-PUD systems such as the one described here are believed to be of great interest for multiple applications, e.g., adhesives, paints, anticorrosion, or dentistry. PMID:26491881

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

    PubMed

    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

  19. Design, synthesis, antiviral and cytostatic activity of ω-(1H-1,2,3-triazol-1-yl)(polyhydroxy)alkylphosphonates as acyclic nucleotide analogues.

    PubMed

    Głowacka, Iwona E; Balzarini, Jan; Andrei, Graciela; Snoeck, Robert; Schols, Dominique; Piotrowska, Dorota G

    2014-07-15

    The efficient synthesis of a new series of polyhydroxylated dibenzyl ω-(1H-1,2,3-triazol-1-yl)alkylphosphonates as acyclic nucleotide analogues is described starting from dibenzyl ω-azido(polyhydroxy)alkylphosphonates and selected alkynes under microwave irradiation. Selected O,O-dibenzylphosphonate acyclonucleotides were transformed into the respective phosphonic acids. All compounds were evaluated in vitro for activity against a broad variety of DNA and RNA viruses and for cytostatic activity against murine leukemia L1210, human T-lymphocyte CEM and human cervix carcinoma HeLa cells. Compound (1S,2S)-16b exhibited antiviral activity against Influenza A H3N2 subtype (EC50=20μM-visual CPE score; EC50=18μM-MTS method; MCC >100μM, CC50 >100μM) in Madin Darby canine kidney cell cultures (MDCK), and (1S,2S)-16k was active against vesicular stomatitis virus and respiratory syncytial virus in HeLa cells (EC50=9 and 12μM, respectively). Moreover, compound (1R,2S)-16l showed activity against both herpes simplex viruses (HSV-1, HSV-2) in HEL cell cultures (EC50=2.9 and 4μM, respectively) and feline herpes virus in CRFK cells (EC50=4μM) but at the same time it exhibited cytotoxicity toward uninfected cell (MCC⩾4μM). Several other compounds have been found to inhibit proliferation of L1210, CEM as well as HeLa cells with IC50 in the 4-50μM range. Among them compounds (1S,2S)- and (1R,2S)-16l were the most active (IC50 in the 4-7μM range). PMID:24906510

  20. Acyclic and star colorings of joins of graphs and an algorithm for cographs.

    SciTech Connect

    Lyons, A.; Mathematics and Computer Science; Univ. of Chicago

    2009-01-01

    An acyclic coloring of a graph is a proper vertex coloring such that the subgraph induced by the union of any two color classes is a disjoint collection of trees. The more restricted notion of star coloring requires that the union of any two color classes induces a disjoint collection of stars. The acyclic and star chromatic numbers of a graph G are defined analogously to the chromatic number {chi}(G) and are denoted by {chi}{sub a}(G) and {chi}{sub s}(G), respectively. In this paper, we consider acyclic and star colorings of graphs that are decomposable with respect to the join operation, which builds a new graph from a collection of two or more disjoint graphs by adding all possible edges between them. In particular, we present a recursive formula for the acyclic chromatic number of joins of graphs and show that a similar formula holds for the star chromatic number. We also demonstrate the algorithmic implications of our results for the cographs, which have the unique property that they are recursively decomposable with respect to the join and disjoint union operations.

  1. 40 CFR 721.10243 - Phosphonic acid, P-[2-[bis(2-hydroxyethyl)amino]ethyl]-, bis(2-chloroethyl) ester.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Phosphonic acid, P- ethyl]-, bis(2... Specific Chemical Substances § 721.10243 Phosphonic acid, P- ethyl]-, bis(2-chloroethyl) ester. (a... phosphonic acid, P- ethyl]-, bis(2-chloroethyl) ester (PMN P-09-193; CAS No. 55088-28-3) is subject...

  2. 40 CFR 721.10243 - Phosphonic acid, P-[2-[bis(2-hydroxyethyl)amino]ethyl]-, bis(2-chloroethyl) ester.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Phosphonic acid, P- ethyl]-, bis(2... Specific Chemical Substances § 721.10243 Phosphonic acid, P- ethyl]-, bis(2-chloroethyl) ester. (a... phosphonic acid, P- ethyl]-, bis(2-chloroethyl) ester (PMN P-09-193; CAS No. 55088-28-3) is subject...

  3. 40 CFR 721.10243 - Phosphonic acid, P-[2-[bis(2-hydroxyethyl)amino]ethyl]-, bis(2-chloroethyl) ester.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Phosphonic acid, P- ethyl]-, bis(2... Specific Chemical Substances § 721.10243 Phosphonic acid, P- ethyl]-, bis(2-chloroethyl) ester. (a... phosphonic acid, P- ethyl]-, bis(2-chloroethyl) ester (PMN P-09-193; CAS No. 55088-28-3) is subject...

  4. Hypouricemic effects of novel concentrative nucleoside transporter 2 inhibitors through suppressing intestinal absorption of purine nucleosides.

    PubMed

    Hiratochi, Masahiro; Tatani, Kazuya; Shimizu, Kazuo; Kuramochi, Yu; Kikuchi, Norihiko; Kamada, Noboru; Itoh, Fumiaki; Isaji, Masayuki

    2012-09-01

    We have developed concentrative nucleoside transporter 2 (CNT2) inhibitors as a novel pharmacological approach for improving hyperuricemia by inhibiting intestinal absorption of purines. Dietary purine nucleosides are absorbed in the small intestines by CNTs expressed in the apical membrane. In humans, the absorbed purine nucleosides are rapidly degraded to their final end product, uric acid, by xanthine oxidase. Based on the expression profile of human CNTs in digestive tract tissues, we established a working hypothesis that mainly CNT2 contributes to the intestinal absorption of purine nucleosides. In order to confirm this possibility, we developed CNT2 inhibitors and found that (2R,3R,4S,5R)-2-(6-amino-8-{[3'-(3-aminopropoxy)-biphenyl-4-ylmethyl]-amino}-9H-purin-9-yl)-5-hydroxymethyl-tetrahydrofuran-3,4-diol (KGO-2142) and 1-[3-(5-{[1-((2R,3R,4S,5R)-3,4-dihydroxy-5-hydroxymethyl-tetrahydrofuran-2-yl)-1H-benzimidazol-2-ylamino]-methyl}-2-ethoxyphenoxy)-propyl]-piperidine-4-carboxylic acid amide (KGO-2173) were inhibitory. These CNT2 inhibitors had potent inhibitory activity against inosine uptake via human CNT2, but they did not potently interfere with nucleoside uptake via human CNT1, CNT3 or equilibrative nucleoside transporters (ENTs) in vitro. After oral administration of KGO-2173 along with [(14)C]-inosine, KGO-2173 significantly decreased the urinary excretion of radioactivity at 6 and 24h in rats. Since dietary purine nucleosides are not utilized in the body and are excreted into the urine rapidly, this decrease in radioactivity in the urine represented the inhibitory activity of KGO-2173 toward the absorption of [(14)C]-inosine in the small intestines. KGO-2142 almost completely inhibited dietary RNA-induced hyperuricemia and the increase in urinary excretion of uric acid in cebus monkeys. These novel CNT2 inhibitors, KGO-2142 and KGO-2173, could be useful therapeutic options for the treatment of hyperuricemia. PMID:22709993

  5. A New Epoxy Bis-Phosphonate Crosslinker for Durable Fire Retardancy on Cotton

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A new epoxy bis-phosphonate crosslinker for cotton [2-(dimethoxy-phosphorylmethyl)-oxiranylmethyl]-phosphonic acid dimethyl ester was prepared in two steps from 3-chloro-2-chloromethylpropene in 55% yield. The new monomer was characterized by proton and carbon NMR and GC-mass spectrometry. This cro...

  6. Phosphonate removal from discharged circulating cooling water using iron-carbon micro-electrolysis.

    PubMed

    Zhou, Zhen; Qiao, Weimin; Lin, Yangbo; Shen, Xuelian; Hu, Dalong; Zhang, Jianqiao; Jiang, Lu-Man; Wang, Luochun

    2014-01-01

    Phosphonate is a commonly used corrosion and scale inhibitor for a circulating cooling water (CCW) system. Its discharge could cause eutrophication of receiving waters. The iron-carbon (Fe/C) micro-electrolysis technology was used to degrade and remove phosphonate from discharged CCW. The influences of initial pH, Fe/C ratio (FCR) and temperature on phosphonate removal were investigated in a series of batch tests and optimized by response surface methodology. The quadratic model of phosphonate removal was obtained with satisfactory degrees of fitness. The optimum conditions with total phosphorus removal efficiency of 95% were obtained at pH 7.0, FCR of 1.25, and temperature of 45 °C. The phosphonate removal mechanisms were also studied. Phosphonate removal occurred predominantly via two consecutive reactive phases: the degradation of phosphonate complexes (Ca-phosphonate) and the precipitation of Fe/C micro-electrolysis products (PO₄(3-), Ca²⁺ and Fe³⁺). PMID:25098884

  7. Structural variation in cation-assisted assembly of high-nuclearity Mn arsonate and phosphonate wheels.

    PubMed

    Chimamkpam, Theresa O; Clérac, Rodolphe; Mitcov, Dmitri; Twamley, Brendan; Venkatesan, Munuswamy; Schmitt, Wolfgang

    2016-01-28

    Comproportionation reactions between MnCl2 and KMnO4 in the presence of arsonate or phosphonate ligands promote the cation-assisted assembly of high-nuclearity, wheel-shaped or toroidal {Mn8} () and {Mn24} () complexes; the closely corresponding reaction systems provide insights into the complexation behaviour of homologous phosphonate/arsonate ligand species. PMID:26740231

  8. 40 CFR 721.10370 - Phosphonic acid, p-octyl-, lanthanum (3+) salt (2:1).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Phosphonic acid, p-octyl-, lanthanum... New Uses for Specific Chemical Substances § 721.10370 Phosphonic acid, p-octyl-, lanthanum (3+) salt... substance identified as phosphinic acid, p-octyl-, lanthanum (3+) salt (2:1) (PMN P-10-99; CAS No....

  9. 40 CFR 721.10370 - Phosphonic acid, p-octyl-, lanthanum (3+) salt (2:1).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Phosphonic acid, p-octyl-, lanthanum... New Uses for Specific Chemical Substances § 721.10370 Phosphonic acid, p-octyl-, lanthanum (3+) salt... substance identified as phosphinic acid, p-octyl-, lanthanum (3+) salt (2:1) (PMN P-10-99; CAS No....

  10. 40 CFR 721.10370 - Phosphonic acid, p-octyl-, lanthanum (3+) salt (2:1).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Phosphonic acid, p-octyl-, lanthanum... New Uses for Specific Chemical Substances § 721.10370 Phosphonic acid, p-octyl-, lanthanum (3+) salt... substance identified as phosphinic acid, p-octyl-, lanthanum (3+) salt (2:1) (PMN P-10-99; CAS No....

  11. Carbocyclic pyrimidine nucleosides as inhibitors of S-adenosylhomocysteine hydrolase.

    PubMed

    Mosley, Sylvester L; Bakke, Brian A; Sadler, Joshua M; Sunkara, Naresh K; Dorgan, Kathleen M; Zhou, Zhaohui Sunny; Seley-Radtke, Katherine L

    2006-12-01

    The design, synthesis, and unexpected inhibitory activity against S-adenosyl-homocysteine (SAH) hydrolase (SAHase, EC 3.3.1.1) for a series of truncated carbocyclic pyrimidine nucleoside analogues is presented. Of the four nucleosides obtained, 10 was found to be active with a Ki value of 5.0 microM against SAHase. PMID:16904326

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

    PubMed

    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. PMID:27498231

  13. [Synthesis and biological properties of α-thymidine 5'-aryl phosphonates].

    PubMed

    Ivanov, M A; Karpenko, I L; Chernousova, L N; Andreevskaia, S N; Smirnova, T G; Aleksandrova, L A

    2013-01-01

    The interaction of CDI-activated diethyl phosphonoacetate with methyl 4-aminobenzoat or 3,5-difluoromethylphenylamine followed by treatment with Me3SiBr in DMF led to N-aryl aminocarbonylmethyl phosphonates and their ethyl esters. Their coupling with 3'-acetyl-α-thymidine followed by removal of the acetyl groups gave (α-D-thymidine-5'-il) N-[4-(methoxycarbonyl-, aminocarbonyl- and carboxy)phenyl]-aminocarbonylmethyl phosphonates, (α-D-thymidine-5'-il)-[3,5-bis(trifluoromethyl)phenylaminocarbonyl]methyl phosphonate and their ethyl esters. The phosphonates were stable in different conditions, low cytotoxic (in Vero and K562 cells) and were able to penetrate into K562 cells. The only ethyl ester of (α-D-thymidine-5'-il) N-[4-(methoxycarbonyl)phenyl]-aminocarbonylmethyl phosphonate in high concentration (200 μg/mL) inhibited in vitro the growth of laboratory sensitive strain of Mycobacterium tuberculosis H37Rv. PMID:25696933

  14. Phosphonate analogues of cyclopropavir phosphates and their E-isomers. Synthesis and antiviral activity.

    PubMed

    Mhaske, Santosh B; Ksebati, Bashar; Prichard, Mark N; Drach, John C; Zemlicka, Jiri

    2009-06-01

    Z- and E-Phosphonate analogues 12 and 13 derived from cyclopropavir and the corresponding cyclic phosphonates 14 and 15 were synthesized and their antiviral activity was investigated. The 2,2-bis(hydroxymethylmethylenecyclopropane acetate (17) was transformed to tetrahydropyranyl acetate 18. Deacetylation gave intermediate 19 which was converted to bromide 20. Alkylation with diisopropyl methylphosphonate afforded after protecting group exchange (21 to 22) acetylated phosphonate intermediate 22. Addition of bromine gave the dibromo derivative 16 which was used in the alkylation-elimination procedure with 2-amino-6-chloropurine to give Z- and E-isomers 23 and 24. Hydrolytic dechlorination coupled with removal of all protecting groups gave the guanine phosphonates 12 and 13. Cyclization afforded the cyclic phosphonates 14 and 15. Z-Phosphonate 12 was a potent and non-cytotoxic inhibitor of human and murine cytomegalovirus (HCMV and MCMV) with EC(50) 2.2-2.7 and 0.13 microM, respectively. It was also an effective agent against Epstein-Barr virus (EBV, EC(50) 3.1 microM). The cyclic phosphonate 14 inhibited HCMV (EC(50) 2.4-11.5 microM) and MCMV (EC(50) 0.4 microM) but it was ineffective against EBV. Both phosphonates 12 and 14 were as active against two HCMV Towne strains with mutations in UL97 as they were against wild-type HCMV thereby circumventing resistance due to such mutations. Z-Phosphonate 12 was a moderate inhibitor of replication of herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) but it was a potent agent against varicella zoster virus (VZV, EC(50) 2.9 microM). The cyclic phosphonate 14 lacked significant potency against these viruses. E-isomers 13 and 15 were devoid of antiviral activity. PMID:19410465

  15. Phosphonate Analogues of Cyclopropavir Phosphates and Their E-isomers. Synthesis and Antiviral Activity

    PubMed Central

    Mhaske, Santosh B.; Ksebati, Bashar; Prichard, Mark N.; Drach, John C.; Zemlicka, Jiri

    2009-01-01

    Z- and E-phosphonate analogues 12 and 13 derived from cyclopropavir and the corresponding cyclic phosphonates 14 and 15 were synthesized and their antiviral activity was investigated. The 2,2-bis(hydroxymethylmethylenecyclopropane acetate (17) was transformed to tetrahydropyranyl acetate 18. Deacetylation gave intermediate 19 which was converted to bromide 20. Alkylation with diisopropyl methylphosphonate afforded after protecting group exchange (21 to 22) acetylated phosphonate intermediate 22. Addition of bromine gave the dibromo derivative 16 which was used in the alkylation-elimination procedure with 2-amino-6-chloropurine to give Z- and E-isomers 23 and 24. Hydrolytic dechlorination coupled with removal of all protecting groups gave the guanine phosphonates 12 and 13. Cyclization afforded the cyclic phosphonates 14 and 15. Z-Phosphonate 12 was a potent and non-cytotoxic inhibitor of human and murine cytomegalovirus (HCMV and MCMV) with EC50 2.2-2.7 and 0.13 μM, respectively. It was also an effective agent against Epstein-Barr virus (EBV, EC50 3.1 μM). The cyclic phosphonate 14 inhibited HCMV (EC50 2.4-11.5 μM) and MCMV (EC50 0.4 μM) but it was ineffective against EBV. Both phosphonates 12 and 14 were as active against two HCMV Towne strains with mutations in UL97 as they were against wild-type HCMV thereby circumventing resistance due to such mutations. Z-Phosphonate 12 was a moderate inhibitor of replication of herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) but it was a potent agent against varicella zoster virus (VZV, EC50 2.9 μM). The cyclic phosphonate 14 lacked significant potency against these viruses. E-isomers 13 and 15 were devoid of antiviral activity. PMID:19410465

  16. (Biological applications of nucleosides and nucleotides)

    SciTech Connect

    Srivastava, P.C.

    1990-08-20

    The traveler was invited to visit The Meditech Group, VTT Technology, Inc., Reactor Laboratory, VTT Technical Research Center of Finland (VTT), Otakaari, Espoo, Finland. The Meditech Group commands a 70 percent market share of Finland's radiopharmaceutical business and plans to expand its activities to other Scandinavian countries as well as in the Leningrad area of USSR. Meditech has plans to separate itself from Technical Research Center of Finland and its subsidiary VTT Technology, Inc., to become a private radiopharmaceutical company in the near future. As a private company, Meditech could expand its activities to encompass radiopharmaceutical research and development and may require foreign technical experts to support its research endeavors. The traveler also attended the Ninth International Round Table Conference on Nucleosides, Nucleotides, and Their Biological Applications held at the Biomedical Center, University of Uppsala, Uppsala, Sweden. The meeting focused on the chemistry and biology of RNA and DNA and their building blocks, nucleosides and nucleotides. The traveler also presented an invited paper entitled Design, Synthesis and Tumor Specificity of Azomycin Ribo- and Acyclonucleosides,'' describing his recent work at Oak Ridge National Laboratory.

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

    PubMed

    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

  18. Products of the direct reaction of the diazonium ion of a metabolite of the carcinogen N-nitrosomorpholine with purines of nucleosides and DNA.

    PubMed

    Zink, Charles N; Soissons, Nicolas; Fishbein, James C

    2010-07-19

    A number of putative purine nucleoside and nucleobase adducts of the diazonium ion derived from 3-hydroxy-N-nitrosomorpholine have been synthesized as dimethylacetals. These are converted, in most cases nearly quantitatively, to the aldehydes, or in two cases to their derivatives, on treatment with mild acid to yield standards for a quantitative investigation of alkylation of purine nucleosides and DNA by the above metabolite of the powerful carcinogen N-nitrosomorpholine. The stability of the resulting nucleobase ethoxyacetaldehyde (EA) adducts has been characterized under a number of conditions with respect to their propensity to decompose. The stabilities, compared to that of the previously characterized adduct of the model benzimidazole, are generally unexceptional. Deposition of adducts on purine nucleosides and DNA were quantified in reactions in which 3-hydroperoxy-N-nitrosomorpholine was reduced to the hydroxy metabolite by a water-soluble phosphine at 21 +/- 2 degrees C. The adduct profile is highly similar to that observed from simpler alpha-hydroxy metabolites of acyclic dialkylnitrosamines, with the three most abundant ethoxyacetaldehyde (EA) adducts in reactions of duplex DNA being N7-EA-Gua approximately O(6)-EA-Gua > N3-EA-Ade. The initial rate kinetics of formation of hydroxyethyl (HE) lesions from the initially formed EA lesions have been determined in the case of the major products in the cases of both the nucleoside and DNA adducts. The rates of formation of HE adducts are accelerated in DNA, relative to the nucleosides in the cases of the N7-EA-Ade, N7-EA-Gua, and O(6)-EA-Gua adducts by factors of 7, 14, and 54, respectively. The initial rates of depurination of the N3-EA-Ade, N7-EA-Gua, and N7-EA-Gua adducts have also been quantified, and they are unexceptional in comparison with what has been previously reported for simple alkyl adducts. The adduct profiles reported here stand in significant contrast to what has been reported previously for

  19. Adsorption and removal kinetics of phosphonate from water using natural adsorbents.

    PubMed

    Kumar, R Anil; Velayudhan, K T; Ramachandran, V; Bhai, R Susheela; Unnikrishnan, G; Vasu, K

    2010-01-01

    The removal of phosphonate from water was studied using some natural adsorbents. Potassium phosphonate is a fungicide used for the control of Phytophthora capsici, which is prevalent in black pepper (Piper nigrum L.). Batch adsorption kinetic experiments were conducted on the adsorption of phosphonate onto the adsorbents. The concentration of phosphonate was measured on a high-performance liquid chromatograph fitted with a conductivity detector. The percentage removal of phosphonate by powdered laterite stone (PLS) from water was 40.4%, within a residence time of 15 minutes. The mechanisms of the rate of adsorption were analyzed and compared using the pseudo-second-order, Elovich, and intraparticle diffusion models. The experimental data was found to correlate well with the pseudo-second-order kinetic model, indicating adsorption as a chemisorption process. A possible reaction in the phosphonate-PLS system also has been proposed. The PLS can be used as a low-cost natural adsorbent for phosphonate removal from water. PMID:20112539

  20. Phosphonate utilization by the globally important marine diazotroph Trichodesmium.

    PubMed

    Dyhrman, S T; Chappell, P D; Haley, S T; Moffett, J W; Orchard, E D; Waterbury, J B; Webb, E A

    2006-01-01

    The factors that control the growth and nitrogen fixation rates of marine diazotrophs such as Trichodesmium have been intensively studied because of the role that these processes have in the global cycling of carbon and nitrogen, and in the sequestration of carbon to the deep sea. Because the phosphate concentrations of many ocean gyres are low, the bioavailability of the larger, chemically heterogeneous pool of dissolved organic phosphorus could markedly influence Trichodesmium physiology. Here we describe the induction, by phosphorus stress, of genes from the Trichodesmium erythraeum IMS101 genome that are predicted to encode proteins associated with the high-affinity transport and hydrolysis of phosphonate compounds by a carbon-phosphorus lyase pathway. We show the importance of these genes through expression analyses with T. erythraeum from the Sargasso Sea. Phosphonates are known to be present in oligotrophic marine systems, but have not previously been considered to be bioavailable to marine diazotrophs. The apparent absence of genes encoding a carbon-phosphorus lyase pathway in the other marine cyanobacterial genomes suggests that, relative to other phytoplankton, Trichodesmium is uniquely adapted for scavenging phosphorus from organic sources. This adaptation may help to explain the prevalence of Trichodesmium in low phosphate, oligotrophic systems. PMID:16397497

  1. Development of Oseltamivir Phosphonate Congeners as Anti-Influenza Agents

    PubMed Central

    Cheng, Ting-Jen R.; Weinheimer, Steven; Tarbet, E. Bart; Jan, Jia-Tsrong; Cheng, Yih-Shyun E.; Shie, Jiun-Jie; Chen, Chun-Lin; Chen, Chih-An; Hsieh, Wei-Che; Huang, Pei-Wei; Lin, Wen-Hao; Wang, Shi-Yun; Fang, Jim-Min; Hu, Oliver Yoa-Pu; Wong, Chi-Huey

    2012-01-01

    Oseltamivir phosphonic acid (tamiphosphor, 3a), its monoethyl ester (3c), guanidino-tamiphosphor (4a) and its monoethyl ester (4c) are potent inhibitors of influenza neuraminidases. They inhibit the replication of influenza viruses, including the oseltamivir-resistant H275Y strain, at low nM to pM levels, and significantly protect mice from infection with lethal doses of influenza viruses when orally administered with 1 mg/kg or higher doses. These compounds are stable in simulated gastric fluid, liver microsomes and human blood, and are largely free from binding to plasma proteins. Pharmacokinetic properties of these inhibitors are thoroughly studied in dogs, rats and mice. The absolute oral bioavailability of these compounds was lower than 12%. No conversion of monoester 4c to phosphonic acid 4a was observed in rats after intravenous administration, but partial conversion of 4c was observed with oral administration. Advanced formulation may be investigated to develop these new anti-influenza agents for better therapeutic use. PMID:23009169

  2. Cascade Cyclizations of Acyclic and Macrocyclic Alkynones: Studies toward the Synthesis of Phomactin A

    PubMed Central

    Ciesielski, Jennifer; Gandon, Vincent; Frontier, Alison J.

    2013-01-01

    A study of the reactivity and diastereoselectivity of the Lewis acid-promoted cascade cyclizations of both acyclic and macrocyclic alkynones is described. In these reactions, a β-iodoallenolate intermediate is generated via conjugate addition of iodide to an alkynone, followed by an intramolecular aldol reaction with a tethered aldehyde to afford a cyclohexenyl alcohol. The Lewis acid magnesium iodide (MgI2) was found to promote irreversible ring closure, while cyclizations using BF3·OEt2 as promoter occurred reversibly. For both acyclic and macrocyclic ynones, high diastereoselectivity was observed in the intramolecular aldol reaction. The MgI2 protocol for cyclization was applied to the synthesis of advanced intermediates relevant to the synthesis of phomactin natural products, during which a novel transannular cation-olefin cyclization was observed. DFT calculations were conducted to analyze the mechanism of this unusual MgI2-promoted process. PMID:23724905

  3. Acyclic monoterpenes in tree essential oils as a shrinking agent for waste-expanded polystyrene.

    PubMed

    Shimotori, Yasutaka; Hattori, Kazuyuki; Aoyama, Masakazu; Miyakoshi, Tetsuo

    2011-01-01

    We examined the dissolution of polystyrene (PS) into acyclic monoterpenes present in tree essential oils, to develop an environmentally friendly shrinking agent for waste-expanded polystyrene (EPS). The dissolving powers of geranyl acetate, geranylacetone, and geranyl formate [221.8-241.2 g PS (100 g solvent)(-1)] compared favorably with that of (R)-limonene [181.7 g PS (100 g solvent)(-1)]. Their favorable dissolving powers for PS can be explained by their flexible linear structures, which may be more accessible to the inside of bulk PS compared with cyclic monoterpenes. These acyclic monoterpenes and PS were recovered almost quantitatively by simple steam distillation of the PS solution. PMID:21644162

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

    PubMed

    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

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

    PubMed

    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

  6. Natural and engineered biosynthesis of nucleoside antibiotics in Actinomycetes.

    PubMed

    Chen, Wenqing; Qi, Jianzhao; Wu, Pan; Wan, Dan; Liu, Jin; Feng, Xuan; Deng, Zixin

    2016-03-01

    Nucleoside antibiotics constitute an important family of microbial natural products bearing diverse bioactivities and unusual structural features. Their biosynthetic logics are unique with involvement of complex multi-enzymatic reactions leading to the intricate molecules from simple building blocks. Understanding how nature builds this family of antibiotics in post-genomic era sets the stage for rational enhancement of their production, and also paves the way for targeted persuasion of the cell factories to make artificial designer nucleoside drugs and leads via synthetic biology approaches. In this review, we discuss the recent progress and perspectives on the natural and engineered biosynthesis of nucleoside antibiotics. PMID:26153500

  7. Triphosgene-Pyridine Mediated Stereoselective Chlorination of Acyclic Aliphatic 1,3-Diols†

    PubMed Central

    Villalpando, Andrés; Saputra, Mirza A.; Tugwell, Thomas H.; Kartika, Rendy

    2015-01-01

    We describe a strategy to chlorinate stereocomplementary acyclic aliphatic 1,3-diols using a mixture of triphosgene and pyridine. While 1,3-anti diols readily led to 1,3-anti dichlorides, 1,3-syn diols must be converted to 1,3-syn diol monosilylethers to access the corresponding 1,3-syn dichlorides. These dichlorination protocols were operationally simple, very mild, and readily tolerated by advanced synthetic intermediates. PMID:26323232

  8. Hepatotoxicity of nucleoside reverse transcriptase inhibitors.

    PubMed

    Montessori, Valentina; Harris, Marianne; Montaner, Julio S G

    2003-05-01

    Hepatotoxicity is an adverse effect of all available classes of antiretrovirals, including nucleoside reverse transcriptase inhibitors (NRTI). A syndrome of hepatic steatosis and lactic acidosis has been recognized as a rare, potentially fatal complication since the advent of NRTI monotherapy in the early 1990s. Today, NRTI remain the backbone of antiretroviral combination regimens, and, with the success of current treatment strategies, exposure to two or more of these agents may occur over a number of years. Hepatic steatosis and lactic acidosis are accordingly being observed more frequently, along with a more recently recognized syndrome of chronic hyperlactatemia. These as well as other adverse effects of NRTI are mediated by inhibition of human DNA polymerase gamma, resulting in mitochondrial dysfunction in the liver and other tissues. Early recognition and intervention are essential to avert serious outcomes. PMID:12800069

  9. Functional non-nucleoside adenylyl cyclase inhibitors.

    PubMed

    Lelle, Marco; Hameed, Abdul; Ackermann, Lisa-Maria; Kaloyanova, Stefka; Wagner, Manfred; Berisha, Filip; Nikolaev, Viacheslav O; Peneva, Kalina

    2015-05-01

    In this study, we describe the synthesis of novel functional non-nucleoside adenylyl cyclase inhibitors, which can be easily modified with thiol containing biomolecules such as tumour targeting structures. The linkage between inhibitor and biomolecule contains cleavable bonds to enable efficient intracellular delivery in the reductive milieu of the cytosol as well as in the acidic environment within endosomes and lysosomes. The suitability of this synthetic approach was shown by the successful bioconjugation of a poor cell-permeable inhibitor with a cell-penetrating peptide. Additionally, we have demonstrated the excellent inhibitory effect of the compounds presented here in a live-cell Förster resonance energy transfer-based assay in human embryonic kidney cells. PMID:25319071

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

    SciTech Connect

    Johnson, Zachary Lee; Cheong, Cheom-Gil; Lee, Seok-Yong

    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.

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

    PubMed

    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

  12. Nucleoside transporter expression and function in cultured mouse astrocytes.

    PubMed

    Peng, Liang; Huang, Rong; Yu, Albert C H; Fung, King Y; Rathbone, Michel P; Hertz, Leif

    2005-10-01

    Uptake of purine and pyrimidine nucleosides in astrocytes is important for several reasons: (1) uptake of nucleosides contributes to nucleic acid synthesis; (2) astrocytes synthesize AMP, ADP, and ATP from adenosine and GTP from guanosine; and (3) adenosine and guanosine function as neuromodulators, whose effects are partly terminated by cellular uptake. It has previously been shown that adenosine is rapidly accumulated by active uptake in astrocytes (Hertz and Matz, Neurochem Res 14:755-760, 1989), but the ratio between active uptake and metabolism-driven uptake of adenosine is unknown, as are uptake characteristics for guanosine. The present study therefore aims at providing detailed information of nucleoside transport and transporters in primary cultures of mouse astrocytes. Reverse transcription-polymerase chain reaction identified the two equilibrative nucleoside transporters, ENT1 and ENT2, together with the concentrative nucleoside transporter CNT2, whereas CNT3 was absent, and CNT1 expression could not be investigated. Uptake studies of tritiated thymidine, formycin B, guanosine, and adenosine (3-s uptakes at 1-4 degrees C to study diffusional uptake and 1-60-min uptakes at 37 degrees C to study concentrative uptake) demonstrated a fast diffusional uptake of all four nucleosides, a small, Na(+)-independent and probably metabolism-driven uptake of thymidine (consistent with DNA synthesis), larger metabolism-driven uptakes of guanosine (consistent with synthesis of DNA, RNA, and GTP) and especially of adenosine (consistent with rapid nucleotide synthesis), and Na(+)-dependent uptakes of adenosine (consistent with its concentrative uptake) and guanosine, rendering neuromodulator uptake independent of nucleoside metabolism. Astrocytes are accordingly well suited for both intense nucleoside metabolism and metabolism-independent uptake to terminate neuromodulator effects of adenosine and guanosine. PMID:15892125

  13. Synthesis and Evaluation of 2'-Deoxy-2'-Spirodiflurocyclopropyl Nucleoside Analogs.

    PubMed

    Liu, Xiao; Xia, Xueliang; Sun, Chenghai; Lin, Cai; Zhou, Yiqian; Hussain, Muzammal; Tang, Fei; Liu, Lu; Li, Xue; Zhang, Jiancun

    2016-09-01

    The preparation of 2'-deoxy-2'-siprodifluorocyclopropany-lnucleoside analogs has been achieved from α-d-glucose in several steps. The key step in the synthesis was the introduction of the difluorocyclopropane through a difluorocarbene type reaction at the 2'-position. Then, a series of novel 2'-deoxy-2'-spirodifluorocyclopropanyl nucleoside analogs were synthesized using the Vorbrüggen method. All the synthesized nucleosides were characterized and subsequently evaluated against hepatitis C and influenza A virus strains in vitro. PMID:27556785

  14. Distribution of nucleosides in populations of Cordyceps cicadae.

    PubMed

    Zeng, Wen-Bo; Yu, Hong; Ge, Feng; Yang, Jun-Yuan; Chen, Zi-Hong; Wang, Yuan-Bing; Dai, Yong-Dong; Adams, Alison

    2014-01-01

    A rapid HPLC method had been developed and used for the simultaneous determination of 10 nucleosides (uracil, uridine, 2'-deoxyuridine, inosine, guanosine, thymidine, adenine, adenosine, 2'-deoxyadenosine and cordycepin) in 10 populations of Cordyceps cicadae, in order to compare four populations of Ophicordyceps sinensis and one population of Cordyceps militaris. Statistical analysis system (SAS) 8.1 was used to analyze the nucleoside data. The pattern of nucleoside distribution was analyzed in the sampled populations of C. cicadae, O. sinensis and C. militaris, using descriptive statistical analysis, nested analysis and Q cluster analysis. The total amount of the 10 nucleosides in coremium was 1,463.89-5,678.21 µg/g in 10 populations of C. cicadae, 1,369.80-3,941.64 µg/g in sclerotium. The average contents of the 10 analytes were 4,392.37 µg/g and 3,016.06 µg/g in coremium and sclerotium, respectively. The coefficient of variation (CV) of nucleosides ranged from 8.36% to 112.36% in coremium of C. cicadae, and from 10.77% to 155.87% in sclerotium of C. cicadae. The CV of the nucleosides was wide within C. cicadae populations. The nested variation analysis by the nine nucleosides' distribution indicated that about 42.29% of the nucleoside variability in coremium was attributable to the differentiation among populations, and the remaining 57.71% resided in the populations. It was also shown that about 28.94% of the variation in sclerotium was expressed between populations, while most of the variation (71.06%) corresponded to the populations. PMID:24830714

  15. Transport characteristics of mouse concentrative nucleoside transporter 1.

    PubMed

    Niitani, Miho; Nishida, Kentaro; Okuda, Hiroto; Nagai, Katsuhito; Fujimoto, Sadaki; Nagasawa, Kazuki

    2010-03-30

    Concentrative nucleoside transporter 1 (CNT1, SLC28A1) is a key molecule for determining the pharmacokinetic/pharmacodynamic profile of a candidate compound derived from a pyrimidine nucleoside, but there is no available information on the differences in the functional profile of this ortholog between man and mouse. Here, using a clone of mouse CNT1 (mCNT1), we investigated its transport characteristics and substrate specificity for synthetic nucleoside analogues, and compared them with those of human CNT1 (hCNT1). In mCNT1-transfected Cos-7 cells, pyrimidine, but not purine, nucleosides showed sodium- and concentration-dependent uptake, and uridine uptake was competitively inhibited by uridine analogues, the rank order of the inhibitory effects being 5-bromouridine>3'-deoxyuridine>2'-deoxyuridine. cis- and trans-Inhibition studies involving synthetic nucleoside drugs revealed that gemcitabine and zidovudine greatly inhibited [(3)H]uridine uptake mediated by mCNT1 in the both cases, while cytarabine and zalcitabine showed small cis-inhibitory effect, and no trans-inhibitory effect on the uptake. These results demonstrate that the transport characteristics of mCNT1 are almost the same as those of hCNT1, suggesting that mice may be a good animal model in evaluation of pyrimidine nucleoside analogues as to their applicability in human therapy. PMID:20060452

  16. Expedient and generic synthesis of imidazole nucleosides by enzymatic transglycosylation.

    PubMed

    Vichier-Guerre, S; Dugué, L; Bonhomme, F; Pochet, S

    2016-04-14

    A straightforward route to original imidazole-based nucleosides that makes use of an enzymatic N-transglycosylation step is reported in both the ribo- and deoxyribo-series. To illustrate the scope of this approach, a diverse set of 4-aryl and 4-heteroaryl-1H-imidazoles featuring variable sizes and hydrogen-bonding patterns was prepared using a microwave-assisted Suzuki-Miyaura cross-coupling reaction. These imidazole derivatives were examined as possible substrates for the nucleoside 2'-deoxyribosyltransferase from L. leichmannii and the purine nucleoside phosphorylase from E. coli. The optimum transglycosylation conditions, including the use of co-adjuvants to address solubility issues, were defined. Enzymatic conversion of 4-(hetero)arylimidazoles to 2'-deoxyribo- or ribo-nucleosides proceeded in good to high conversion yields, except bulky hydrophobic imidazole derivatives. Nucleoside deoxyribosyltransferase of class II was found to convert the widest range of functionalized imidazoles into 2'-deoxyribonucleosides and was even capable of bis-glycosylating certain heterocyclic substrates. Our findings should enable chemoenzymatic access to a large diversity of flexible nucleoside analogues as molecular probes, drug candidates and original building blocks for synthetic biology. PMID:26986701

  17. Effects of Perfluorinated Phosphonic Acid Exposure during pregnancy in the mouse

    EPA Science Inventory

    Perfluorinated phosphonic acids (PFPAs) are a member of the perfluoroalkyl acid (PFAA) family, and are structurally similar to the perfluoroalkyl sulfonates and perfluoroalkyl carboxylates. These chemicals have recently been detected in the environment, particularly in surface wa...

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

    PubMed

    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

  19. Biosynthesis of Phosphonic and Phosphinic Acid Natural Products

    PubMed Central

    Metcalf, William W.; van der Donk, Wilfred A.

    2009-01-01

    Natural products containing carbon-phosphorus bonds (phosphonic and phosphinic acids) have found widespread use in medicine and agriculture. Recent years have seen a renewed interest in the biochemistry and biology of these compounds with the cloning of the biosynthetic gene clusters for several family members. This review discusses the commonalities and differences in the molecular logic that lies behind the biosynthesis of these compounds. The current knowledge regarding the metabolic pathways and enzymes involved in the production of a number of natural products, including the approved antibiotic fosfomycin, the widely used herbicide phosphinothricin, and the clinical candidate for treatment of malaria FR900098, is presented. Many of the enzymes involved in the biosynthesis of these compounds catalyze chemically and biologically unprecedented transformations and a wealth of new biochemistry has been revealed through their study. These studies have also suggested new strategies for natural product discovery. PMID:19489722

  20. Graphene phosphonic acid as an efficient flame retardant.

    PubMed

    Kim, Min-Jung; Jeon, In-Yup; Seo, Jeong-Min; Dai, Liming; Baek, Jong-Beom

    2014-03-25

    We report the preparation of graphene phosphonic acid (GPA) via a simple and versatile method and its use as an efficient flame retardant. In order to covalently attach phosphorus to the edges of graphene nanoplatelets, graphite was ball-milled with red phosphorus. The cleavage of graphitic C-C bonds during mechanochemical ball-milling generates reactive carbon species, which react with phosphorus in a sealed ball-mill crusher to form graphene phosphorus. Subsequent opening of the crusher in air moisture leads to violent oxidation of graphene phosphorus into GPA (highest oxidation state). The GPA is readily dispersible in many polar solvents, including neutral water, allowing for solution (spray) coating for high-performance, nontoxic flame-retardant applications. PMID:24575902

  1. Oxygen isotope signature of UV degradation of glyphosate and phosphonoacetate: tracing sources and cycling of phosphonates.

    PubMed

    Sandy, Edward H; Blake, Ruth E; Chang, Sae Jung; Jun, Yao; Yu, Chan

    2013-09-15

    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 CP 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 CP 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. PMID:23892161

  2. A Novel Multi-Phosphonate Surface Treatment of Titanium Dental Implants: A Study in Sheep

    PubMed Central

    von Salis-Soglio, Marcella; Stübinger, Stefan; Sidler, Michéle; Klein, Karina; Ferguson, Stephen J.; Kämpf, Käthi; Zlinszky, Katalin; Buchini, Sabrina; Curno, Richard; Péchy, Péter; Aronsson, Bjorn-Owe; von Rechenberg, Brigitte

    2014-01-01

    The aim of the present study was to evaluate a new multi-phosphonate surface treatment (SurfLink®) in an unloaded sheep model. Treated implants were compared to control implants in terms of bone to implant contact (BIC), bone formation, and biomechanical stability. The study used two types of implants (rough or machined surface finish) each with either the multi-phosphonate Wet or Dry treatment or no treatment (control) for a total of six groups. Animals were sacrificed after 2, 8, and 52 weeks. No adverse events were observed at any time point. At two weeks, removal torque showed significantly higher values for the multi-phosphonate treated rough surface (+32% and +29%, Dry and Wet, respectively) compared to rough control. At 52 weeks, a significantly higher removal torque was observed for the multi-phosphonate treated machined surfaces (+37% and 23%, Dry and Wet, respectively). The multi-phosphonate treated groups showed a positive tendency for higher BIC with time and increased new-old bone ratio at eight weeks. SEM images revealed greater amounts of organic materials on the multi-phosphonate treated compared to control implants, with the bone fracture (from the torque test) appearing within the bone rather than at the bone to implant interface as it occurred for control implants. PMID:25215424

  3. A novel multi-phosphonate surface treatment of titanium dental implants: a study in sheep.

    PubMed

    von Salis-Soglio, Marcella; Stübinger, Stefan; Sidler, Michéle; Klein, Karina; Ferguson, Stephen J; Kämpf, Käthi; Zlinszky, Katalin; Buchini, Sabrina; Curno, Richard; Péchy, Péter; Aronsson, Bjorn-Owe; von Rechenberg, Brigitte

    2014-01-01

    The aim of the present study was to evaluate a new multi-phosphonate surface treatment (SurfLink®) in an unloaded sheep model. Treated implants were compared to control implants in terms of bone to implant contact (BIC), bone formation, and biomechanical stability. The study used two types of implants (rough or machined surface finish) each with either the multi-phosphonate Wet or Dry treatment or no treatment (control) for a total of six groups. Animals were sacrificed after 2, 8, and 52 weeks. No adverse events were observed at any time point. At two weeks, removal torque showed significantly higher values for the multi-phosphonate treated rough surface (+32% and +29%, Dry and Wet, respectively) compared to rough control. At 52 weeks, a significantly higher removal torque was observed for the multi-phosphonate treated machined surfaces (+37% and 23%, Dry and Wet, respectively). The multi-phosphonate treated groups showed a positive tendency for higher BIC with time and increased new-old bone ratio at eight weeks. SEM images revealed greater amounts of organic materials on the multi-phosphonate treated compared to control implants, with the bone fracture (from the torque test) appearing within the bone rather than at the bone to implant interface as it occurred for control implants. PMID:25215424

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

    PubMed Central

    Zhou, Xiaoyue; Park, Shin-Hye; Mao, Hongli; Isoshima, Takashi; Wang, Yi; Ito, Yoshihiro

    2015-01-01

    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. PMID:26366080

  5. Functional characterization of nucleoside transporter gene replacements in Leishmania donovani.

    PubMed

    Liu, Wei; Boitz, Jan M; Galazka, Jon; Arendt, Cassandra S; Carter, Nicola S; Ullman, Buddy

    2006-12-01

    Leishmania donovani express two nucleoside transporters of non-overlapping ligand selectivity. To evaluate the physiological role of nucleoside transporters in L. donovani, homozygous null mutants of the genes encoding the LdNT1 adenosine-pyrimidine nucleoside transporter and the LdNT2 inosine-guanosine transporter were created singly and in combination by single targeted gene replacement followed by selection for loss-of-heterozygosity. The mutant alleles were verified by Southern blotting, and the effects of gene replacement on transport phenotype were evaluated by rapid sampling transport measurements and by drug resistance profiles. The Deltaldnt1, Deltaldnt2, and Deltaldnt1/Deltaldnt2 mutants were all capable of proliferation in defined culture medium supplemented with any of a spectrum of purine nucleobases or nucleosides, except that a Deltaldnt2 lesion conferred an inability to efficiently salvage exogenous xanthosine, a newly discovered ligand of LdNT2. Each of the three knockout strains was viable as promastigotes and axenic amastigotes and capable of maintaining an infection in J774 and bone marrow-derived murine macrophages. These genetic studies demonstrate: (1) that L. donovani promastigotes, axenic amastigotes, and tissue amastigotes are viable in the absence of nucleoside transport; (2) that nucleoside transporters are not essential for sustaining an infection in mammalian host cells; (3) that the phagolysosome of macrophages is likely to contain purines that are not LdNT1 or LdNT2 ligands, i.e., nucleobases. Furthermore, the Deltaldnt1, Deltaldnt2, and Deltaldnt1/Deltaldnt2 knockouts offer a unique genetically defined null background for the biochemical and genetic characterization of nucleoside transporter genes and cDNAs from phylogenetically diverse species and of genetically manipulated LdNT1 and LdNT2 constructs. PMID:17050001

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

    NASA Astrophysics Data System (ADS)

    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

  7. Characterization of cyclic and acyclic alkanes in Forties and Kuwait petroleum crudes

    SciTech Connect

    Jones, D.W. ); Pakdel, H. ); Bartle, K.D. )

    1990-01-01

    Alkane hydrocarbon fractions from Forties (North Sea) and Kuwait petroleum crudes, separated by distillation, solvent extraction and silicagel column chromatography and sub-fractionated by molecular-sieve adsorption, have been examined by gas chromatography (GC), {sup 1}H and {sup 13}C NMR spectroscopy, GC-mass spectrometry (MS) and field desorption (FD)MS. GC indicates that Forties contains rather more acyclic isoprenoids and cyclic alkanes than Kuwait; FDMS of Kuwait shows molecular-weight ranges for mono-, di-, tri-, tetra-, and pentacyclic alkanes. {sup 13}C NMR spectra provide evidence of higher aromatic carbon, C{sub A}, in Forties than Kuwait and longer T{sub 1} relaxation times.

  8. Recent Applications of Acyclic (Diene)iron Complexes and (Dienyl)iron Cations in Organic Synthesis

    PubMed Central

    Chaudhury, Subhabrata

    2009-01-01

    Complexation of (tricarbonyl)iron to an acyclic diene serves to protect the ligand against oxidation, reduction and cycloaddition reactions while the steric bulk of this adjunct serves to direct the approach reagents to unsaturated groups attached to the diene onto the face opposite to iron. Furthermore, the Fe(CO)3 moiety can serve to stabilize carbocation centers adjacent to the diene (i.e. pentadienyl-iron cations). Recent applications of these reactivities to the synthesis of polyene, cyclopropane, cycloheptadiene and cyclohexenone containing natural products or analogs will be presented. PMID:21709767

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

    NASA Astrophysics Data System (ADS)

    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.

  10. A novel intramolecular through-space interaction between F and CN: a strategy for the conformational control of an acyclic system.

    PubMed

    Nishide, K; Hagimoto, Y; Hasegawa, H; Shiro, M; Node, M

    2001-11-21

    X-Ray crystallographic analyses of fluorocyanides anti-1 and 2 revealed a novel intramolecular through-space interaction between F and CN in an acyclic system, which was applied to a stereoselective protonation of acyclic fluorocyanides 2 having flexible conformation. PMID:12240092

  11. Nucleosides Accelerate Inflammatory Osteolysis, Acting as Distinct Innate Immune Activators

    PubMed Central

    Pan, George; Zheng, Rui; Yang, Pingar; Li, Yao; Clancy, John P.; Liu, Jianzhong; Feng, Xu; Garber, David A; Spearman, Paul; McDonald, Jay M

    2015-01-01

    The innate immune system and its components play an important role in the pathogenesis of inflammatory bone destruction. Blockade of inflammatory cytokines does not completely arrest bone erosion, suggesting that other mediators also may be involved in osteolysis. Previously we showed that nucleosides promote osteoclastogenesis and bone-resorption activity in the presence of receptor activator for nuclear factor κB ligand (RANKL) in vitro. The studies described here further demonstrate that selected nucleosides and nucleoside analogues accelerate bone destruction in mice immunized with collagen II alone (CII) but also further enhance bone erosion in mice immunized by collagen II plus complete Freund's adjuvant (CII + CFA). Abundant osteoclasts are accumulated in destructive joints. These data indicate that nucleosides act as innate immune activators distinct from CFA, synergistically accelerating osteoclast formation and inflammatory osteolysis. The potential roles of the surface triggering receptor expressed on myeloid cells (TREM) and the intracellular inflammasome in nucleoside-enhanced osteoclastogenesis have been studied. These observations provide new insight into the pathogenesis and underlying mechanism of bone destruction in inflammatory autoimmune osteoarthritis. PMID:21472777

  12. The inhibition of crystal growth of mirabilite in aqueous solutions in the presence of phosphonates

    NASA Astrophysics Data System (ADS)

    Vavouraki, A. I.; Koutsoukos, P. G.

    2016-02-01

    The formation of sodium sulfate decahydrate (Mirabilite) has been known to cause serious damages to structural materials both of modern and of historical buildings. Methods which can retard or completely suppress the development of mirabilte crystals are urgently needed especially as remedies or preventive measures for the preservation of the built cultural heritage. In the present work we present results on the effect of the presence of phosphonate compounds on the kinetics of crystal growth from aqueous supersaturated solutions at 18 °C using the seeded growth technique. The phosphonate compounds tested differed with respect to the number of ionizable phosphonate groups and with respect to the number of amino groups in the respective molecules. The crystal growth process was monitored by the temperature changes during the exothermic crystallization of mirabilite in the stirred supersaturated solutions. The crystal growth of mirabilite in the presence of: (1-hydroxyethylidene)-1, 1-diphosphonic acid (HEDP), amino tri (methylene phosphonic acid) (ATMP), hexamethylenediaminetetra (methylene)phosphonic acid (HTDMP), and diethylene triamine penta(methylene phosphonic acid)(DETPMP) over a range of concentrations between 0.1-5% w/w resulted in significant decrease of the rates of mirabilite crystal growth. All phosphonic compounds tested reduced the crystallization rates up to 60% in comparison with additive-free solutions. The presence of the test compounds did not cause changes of the mechanism of crystal growth which was surface diffusion controlled, as shown by the second order dependence of the rates of mirabilite crystal growth on the relative supersaturation. The excellent fit of the measured rates to a kinetic Langmuir-type model suggested that the activity of the tested inhibitors could be attributed to the adsorption and subsequent reduction of the active crystal growth sites of the seed crystals. In all cases, the inhibitory activity was reduced with

  13. Synthesis and Structural Studies of Calcium and Magnesium Phosphinate and Phosphonate Compounds

    NASA Astrophysics Data System (ADS)

    Bampoh, Victoria Naa Kwale

    The work presented herein describes synthetic methodologies leading to the design of a wide array of magnesium and calcium based phosphinate and phosphonates with possible applications as bone scaffolding materials or additives to bone cements. The challenge to the chemistry of the alkaline earth phosphonate target compounds includes poor solubility of compounds, and poorly understood details on the control of the metal's coordination environment. Hence, less is known on phosphonate based alkaline earth metal organic frameworks as compared to transition metal phosphonates. Factors governing the challenges in obtaining crystalline, well-defined magnesium and calcium solids lie in the large metal diameters, the absence of energetically available d-orbitals to direct metal geometry, as well as the overall weakness of the metal-ligand bonds. A significant part of this project was concerned with the development of suitable reaction conditions to obtain X-ray quality crystals of the reaction products to allow for structural elucidation of the novel compounds. Various methodologies to aid in crystal growth including hydrothermal methods and gel crystallization were employed. We have used phosphinate and phosphonate ligands with different number of phosphorus oxygen atoms as well as diphosphonates with different linker lengths to determine their effects on the overall structural features. An interesting correlation is observed between the dimensionality of products and the increasing number of donor oxygen atoms in the ligands as we progress from phosphinic acid to the phosphorous acids. As an example, monophosphinate ligand only yielded one-dimensional compounds, whereas the phosphonates crystallize as one and two-dimensional compounds, and the di- and triphosphonate based compounds display two or three-dimensional geometries. This thesis provides a selection of calcium and magnesium compounds with one-dimensional geometry, as represented in a calcium phosphinate to novel

  14. Discovery of phosphonic acid natural products by mining the genomes of 10,000 actinomycetes.

    PubMed

    Ju, Kou-San; Gao, Jiangtao; Doroghazi, James R; Wang, Kwo-Kwang A; Thibodeaux, Christopher J; Li, Steven; Metzger, Emily; Fudala, John; Su, Joleen; Zhang, Jun Kai; Lee, Jaeheon; Cioni, Joel P; Evans, Bradley S; Hirota, Ryuichi; Labeda, David P; van der Donk, Wilfred A; Metcalf, William W

    2015-09-29

    Although natural products have been a particularly rich source of human medicines, activity-based screening results in a very high rate of rediscovery of known molecules. Based on the large number of natural product biosynthetic genes in microbial genomes, many have proposed "genome mining" as an alternative approach for discovery efforts; however, this idea has yet to be performed experimentally on a large scale. Here, we demonstrate the feasibility of large-scale, high-throughput genome mining by screening a collection of over 10,000 actinomycetes for the genetic potential to make phosphonic acids, a class of natural products with diverse and useful bioactivities. Genome sequencing identified a diverse collection of phosphonate biosynthetic gene clusters within 278 strains. These clusters were classified into 64 distinct groups, of which 55 are likely to direct the synthesis of unknown compounds. Characterization of strains within five of these groups resulted in the discovery of a new archetypical pathway for phosphonate biosynthesis, the first (to our knowledge) dedicated pathway for H-phosphinates, and 11 previously undescribed phosphonic acid natural products. Among these compounds are argolaphos, a broad-spectrum antibacterial phosphonopeptide composed of aminomethylphosphonate in peptide linkage to a rare amino acid N(5)-hydroxyarginine; valinophos, an N-acetyl l-Val ester of 2,3-dihydroxypropylphosphonate; and phosphonocystoximate, an unusual thiohydroximate-containing molecule representing a new chemotype of sulfur-containing phosphonate natural products. Analysis of the genome sequences from the remaining strains suggests that the majority of the phosphonate biosynthetic repertoire of Actinobacteria has been captured at the gene level. This dereplicated strain collection now provides a reservoir of numerous, as yet undiscovered, phosphonate natural products. PMID:26324907

  15. Discovery of phosphonic acid natural products by mining the genomes of 10,000 actinomycetes

    PubMed Central

    Ju, Kou-San; Gao, Jiangtao; Doroghazi, James R.; Wang, Kwo-Kwang A.; Thibodeaux, Christopher J.; Li, Steven; Metzger, Emily; Fudala, John; Su, Joleen; Zhang, Jun Kai; Lee, Jaeheon; Cioni, Joel P.; Evans, Bradley S.; Hirota, Ryuichi; Labeda, David P.; van der Donk, Wilfred A.; Metcalf, William W.

    2015-01-01

    Although natural products have been a particularly rich source of human medicines, activity-based screening results in a very high rate of rediscovery of known molecules. Based on the large number of natural product biosynthetic genes in microbial genomes, many have proposed “genome mining” as an alternative approach for discovery efforts; however, this idea has yet to be performed experimentally on a large scale. Here, we demonstrate the feasibility of large-scale, high-throughput genome mining by screening a collection of over 10,000 actinomycetes for the genetic potential to make phosphonic acids, a class of natural products with diverse and useful bioactivities. Genome sequencing identified a diverse collection of phosphonate biosynthetic gene clusters within 278 strains. These clusters were classified into 64 distinct groups, of which 55 are likely to direct the synthesis of unknown compounds. Characterization of strains within five of these groups resulted in the discovery of a new archetypical pathway for phosphonate biosynthesis, the first (to our knowledge) dedicated pathway for H-phosphinates, and 11 previously undescribed phosphonic acid natural products. Among these compounds are argolaphos, a broad-spectrum antibacterial phosphonopeptide composed of aminomethylphosphonate in peptide linkage to a rare amino acid N5-hydroxyarginine; valinophos, an N-acetyl l-Val ester of 2,3-dihydroxypropylphosphonate; and phosphonocystoximate, an unusual thiohydroximate-containing molecule representing a new chemotype of sulfur-containing phosphonate natural products. Analysis of the genome sequences from the remaining strains suggests that the majority of the phosphonate biosynthetic repertoire of Actinobacteria has been captured at the gene level. This dereplicated strain collection now provides a reservoir of numerous, as yet undiscovered, phosphonate natural products. PMID:26324907

  16. Nucleoside transporter expression and adenosine uptake in the rat cochlea.

    PubMed

    Khan, Abdul F; Thorne, Peter R; Muñoz, David J B; Wang, Carol J H; Housley, Gary D; Vlajkovic, Srdjan M

    2007-02-12

    Even though extracellular adenosine plays multiple roles in the cochlea, the mechanisms that control extracellular adenosine concentrations in this organ are unclear. This study investigated the expression of nucleoside transporters and adenosine uptake in the rat cochlea. Reverse transcription-polymerase chain reaction revealed the expression of mRNA transcripts for two equilibrative (ENT1 and ENT2) and two concentrative (CNT1 and CNT2) nucleoside transporters. Exogenous adenosine perfused through the cochlear perilymphatic compartment was taken up by cells lining the compartment. Adenosine uptake was sensitive to changes in extracellular Na concentrations and inhibited by nitrobenzylthioinosine (an adenosine uptake blocker). The study suggests that the bi-directional nucleoside transport supports the uptake and recycling of purines and regulates the activation of adenosine receptors by altering adenosine concentrations in cochlear fluid spaces. PMID:17314663

  17. Brain transfer RNA. II. Analysis of modified nucleosides

    SciTech Connect

    Chaudhary, K.D.; Carrier-Malhotra, L.; Murthy, M.R.

    1982-01-01

    Transfer RNAs were isolated from rat and calf brains and their nucleosides were analysed by tritium derivative technique. Qualitative changes in the minor nucleoside components were compared on the fluorograms which showed differences in the intensities of spots. Cerebellar and cortical tRNAs were also compared, but revealed no significant quantitative differences in their methylated constituants despite 60% higher methyltransferase activity observed in cerebellum compared to cerebral cortex. An overall similarity was noticed between the relative proportions of the major and minor nucleosides of tRNAs derived from rat or calf brain, expressed as mol%. Brain tRNA was also analysed by two-dimensional polyacrylamide gel electrophoresis which showed qualitative and quantitative changes during postnatal development.

  18. Supramolecular gels made from nucleobase, nucleoside and nucleotide analogs.

    PubMed

    Peters, Gretchen Marie; Davis, Jeffery T

    2016-06-01

    Supramolecular or molecular gels are attractive for various applications, including diagnostics, tissue scaffolding and targeted drug release. Gelators derived from natural products are of particular interest for biomedical purposes, as they are generally biocompatible and stimuli-responsive. The building blocks of nucleic acids (i.e. nucleobases, nucleosides, and nucleotides) are desirable candidates for supramolecular gelation as they readily engage in reversible, noncovalent interactions. In this review, we describe a number of organo- and hydrogels formed through the assembly of nucleosides, nucleotides, and their derivatives. While natural nucleosides and nucleotides generally require derivatization to induce gelation, guanosine and its corresponding nucleotides are well known gelators. This unique gelating ability is due to propensity of the guanine nucleobase to self-associate into stable higher-order assemblies, such as G-ribbons, G4-quartets, and G-quadruplexes. PMID:27146863

  19. Flow cytomeric measurement of DNA and incorporated nucleoside analogs

    DOEpatents

    Dolbeare, Frank A.; Gray, Joe W.

    1989-01-01

    A method is provided for simultaneously measuring total cellular DNA and incorporated nucleoside analog. The method entails altering the cellular DNA of cells grown in the presence of a nucleoside analog so that single stranded and double stranded portions are present. Separate stains are used against the two portions. An immunochemical stain is used against the single stranded portion to provide a measure of incorporated nucleoside analog, and a double strand DNA-specific stain is used against the double stranded portion to simultaneously provide a measure of total cellular DNA. The method permits rapid flow cytometric analysis of cell populations, rapid identification of cycling and noncycling subpopulations, and determination of the efficacy of S phase cytotoxic anticancer agents.

  20. Chemoselective N-Deacetylation of Protected Nucleosides and Nucleotides Promoted by Schwartz's Reagent

    PubMed Central

    Ferrari, Valentina; Serpi, Michaela; McGuigan, Christopher; Pertusati, Fabrizio

    2015-01-01

    Protection and deprotection strategies involving the N-acetyl group are widely utilized in nucleoside and nucleotide chemistry. Herein, we present a mild and selective N-deacetylation methodology, applicable to purine and pyrimidine nucleosides, by means of Schwartz's reagent, compatible with most of the common protecting groups used in nucleoside chemistry. PMID:26492555

  1. 40 CFR 721.10244 - Phosphonic acid, P-[2-[bis(2-hydroxyethyl)amino]ethyl]-, 2-[bis(2- chloroethoxy)phosphinyl]ethyl...

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Phosphonic acid, P- ethyl]-, 2- ethyl... New Uses for Specific Chemical Substances § 721.10244 Phosphonic acid, P- ethyl]-, 2- ethyl 2... substance identified as phosphonic acid, P- ethyl]-, 2- ethyl 2-chloroethyl ester (PMN P-09-195; CAS...

  2. 40 CFR 721.10244 - Phosphonic acid, P-[2-[bis(2-hydroxyethyl)amino]ethyl]-, 2-[bis(2- chloroethoxy)phosphinyl]ethyl...

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Phosphonic acid, P- ethyl]-, 2- ethyl... New Uses for Specific Chemical Substances § 721.10244 Phosphonic acid, P- ethyl]-, 2- ethyl 2... substance identified as phosphonic acid, P- ethyl]-, 2- ethyl 2-chloroethyl ester (PMN P-09-195; CAS...

  3. 40 CFR 721.10244 - Phosphonic acid, P-[2-[bis(2-hydroxyethyl)amino]ethyl]-, 2-[bis(2- chloroethoxy)phosphinyl]ethyl...

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Phosphonic acid, P- ethyl]-, 2- ethyl... New Uses for Specific Chemical Substances § 721.10244 Phosphonic acid, P- ethyl]-, 2- ethyl 2... substance identified as phosphonic acid, P- ethyl]-, 2- ethyl 2-chloroethyl ester (PMN P-09-195; CAS...

  4. Luminescent ruthenium(II) bipyridyl-phosphonic acid complexes: pH dependent photophysical behavior and quenching with divalent metal ions

    SciTech Connect

    Montalti, M.; Wadhwa, S.; Kim, W.Y.; Kipp, R.A.; Schmehl, R.H.

    2000-01-10

    The synthesis, redox behavior, and photophysical properties of a series of Ru(II) bipyridyl complexes having diimine ligands with phosphonate and phosphonic acid substituents are presented. The phosphonate-containing ligands examined include diethyl 4-(2,2{prime}-bipyrid-4-yl)benzylphosphonate (bpbzp), diethyl 4(2,2{prime}-bipyrid-4-yl)-phenylphosphonate (bppp), and 4,4{prime}-(diethyl phosphonato)-2,2{prime}bipyridine (bpdp), and the [(bpy){sub 2}Ru(L)](PF{sub 6}){sub 2} complexes of both the diethyl phosphonate and the phosphonic acid were prepared. The Ru(III/II) potentials are more positive for the phosphonate complexes than for the phosphonic acids, and the first reduction is localized on the phosphonate-containing ligand for the bppp and bpdp complexes. The first reduction of the phosphonic acid complexes is at more negative potentials and cannot be distinguished from bpy reduction. For the bppp and bpdp complexes luminescence arises from a Ru(d{pi}) {r{underscore}arrow} bpy-phosphonate ({pi}*) MLCT state; the phosphonic acid complexes luminesce at higher energies from a MLCT state not clearly isolated on one ligand. Iron(III) and copper(II) complex with and very efficiently quench the luminescence of all the phosphonic acid complexes in nonaqueous solvents. The quenching mechanism is discussed on the basis of luminescence decay and picosecond transient absorption measurements.

  5. N-Heterocyclic carbene catalysed 1,6-hydrophosphonylation of p-quinone methides and fuchsones: an atom economical route to unsymmetrical diaryl- and triarylmethyl phosphonates.

    PubMed

    Arde, Panjab; Vijaya Anand, Ramasamy

    2016-06-15

    A convenient organocatalytic approach to access unsymmetrical diaryl- and triarylmethyl phosphonates using NHC as a Brønsted base catalyst is described. This atom-economical protocol enables the installation of phosphonate groups on p-quinone methides and fuchsones through a 1,6-conjugate addition of dialkylphosphites, and the corresponding phosphonates were obtained in excellent yields. PMID:26924164

  6. An atomic force microscopy and molecular simulations study of the inhibition of barite growth by phosphonates

    NASA Astrophysics Data System (ADS)

    Pina, C. M.; Putnis, C. V.; Becker, U.; Biswas, S.; Carroll, E. C.; Bosbach, D.; Putnis, A.

    2004-03-01

    The effect of five phosphonic acids (hydroxyethylene diphosphonic acid, HEDP; nitro trimethyl phosphonic acid, NTMP; methylene diphosphonic acid, MDP; amino methylene phosphonic acid, AMP; and sodium phosphonobutane tricarboxylic acid, PBTC) on the growth of the barite(0 0 1) face has been investigated using atomic force microscopy (AFM). Experimental data have been obtained by in situ measurements of the velocities of barite monomolecular steps growing from solutions with different concentrations of each phosphonic acid. Adsorption isotherms, constructed by plotting individual monomolecular step rates versus inhibitor concentrations, indicate a Langmuir adsorption mechanism in the range of concentrations from 0.5 to 10 μmol/l. Both affinity constants calculated from adsorption isotherms and measurements of growth rates of barite monomolecular steps as a function of inhibitor concentration allowed us to give the following ranking of inhibitor effectiveness: PBTC > NTMP > MDP > HEDP ≫ AMP. Molecular simulations of the interaction of the phosphonic acids with barite(0 0 1) surfaces indicate that only kink sites along monomolecular steps can be considered as possible inhibition sites. This is in agreement with the AFM observations and measurements.

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

    SciTech Connect

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

    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.

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

    PubMed

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

    2010-10-12

    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. PMID:20876132

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

    PubMed

    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

  10. Determination of perfluoroalkyl carboxylic, sulfonic, and phosphonic acids in food.

    PubMed

    Ullah, Shahid; Alsberg, Tomas; Vestergren, Robin; Berger, Urs

    2012-11-01

    A sensitive and accurate method was developed and validated for simultaneous analysis of perfluoroalkyl carboxylic acids, sulfonic acids, and phosphonic acids (PFPAs) at low picograms per gram concentrations in a variety of food matrices. The method employed extraction with acetonitrile/water and cleanup on a mixed-mode co-polymeric sorbent (C8 + quaternary amine) using solid-phase extraction. High-performance liquid chromatographic separation was achieved on a C18 column using a mobile phase gradient containing 5 mM 1-methyl piperidine for optimal chromatographic resolution of PFPAs. A quadrupole time-of-flight high-resolution mass spectrometer operating in negative ion mode was used as detector. Method detection limits were in the range of 0.002 to 0.02 ng g(-1) for all analytes. Sample preparation (extraction and cleanup) recoveries at a spiking level of 0.1 ng g(-1) to a baby food composite were in the range of 59 to 98 %. A strong matrix effect was observed in the analysis of PFPAs in food extracts, which was tentatively assigned to sorption of PFPAs to the injection vial in the solvent-based calibration standard. The method was successfully applied to a range of different food matrices including duplicate diet samples, vegetables, meat, and fish samples. PMID:22955674

  11. Characterization of phosphonic acid binding to zinc oxide

    SciTech Connect

    Hotchkiss, Peter J.; Malicki, Michał; Giordano, Anthony J.; Armstrong, Neal R.; Marder, Seth R.

    2011-01-24

    Radio Frequency (RF) sputter-deposited zinc oxide (ZnO) films have been modified with alkylphosphonic acids in order to study both the binding of the phosphonic acid (PA) group to the ZnO surface and the packing of the alkyl chain. The characterization of these PA-modified ZnO substrates by X-ray photoelectron spectroscopy (XPS), infrared reflection-absorption spectroscopy (IRRAS), atomic force microscopy (AFM) and contact angle measurements is presented herein. The surface modification procedure is straightforward and was adapted from earlier work. XPS analysis shows that oxygen plasma (OP) treatment creates reactive oxygen species on the surface of ZnO, allowing for a more robust binding of PAs to the ZnO surface. IRRAS analysis indicates that octadecylphosphonic acid binds to the ZnO surface in a predominantly tridentate fashion, forming dense, well-packed monolayers with alkyl chains in a fully anti-conformation. AFM and contact angle measurements indicate good surface coverage of the PAs with little to no multilayer formation.

  12. Evolution of an Amino Acid-based Prodrug Approach: Stay Tuned

    PubMed Central

    Krylov, Ivan S.; Kashemirov, Boris A.; Hilfinger, John M.; McKenna, Charles E.

    2013-01-01

    Certain acyclic nucleoside phosphonates (ANPs) such as (S)-HPMPC (cidofovir, Vistide®) and (S)-HPMPA have been shown to be active against a broad spectrum of DNA and retroviruses. However, their poor absorption as well as their toxicity limit the utilization of these therapeutics in the clinic. Nucleoside phosphonates are poorly absorbed primarily due to the presence of the phosphonic acid group, which ionizes at physiological pH. When dosed intravenously they display dose-limiting nephrotoxicity due to their accumulation in the kidney. To overcome these limitations, nucleoside phosphonate prodrug strategies have taken center stage in the development pathway and a number of different approaches are at various stages of development. Our efforts have focused on the development of ANP prodrugs in which a benign amino acid promoiety masks a phosphonate P-OH via a hydroxyl side chain. The design of these prodrugs incorporates multiple chemical groups (the P−X−C linkage, the amino acid stereochemistry, the C-terminal and N-terminal functional groups) that can be been tuned to modify absorption, pharmacokinetic and efficacy properties with the goal of improving overall prodrug performance. PMID:23339402

  13. Inhibition of nucleoside diphosphate kinase in rat liver mitochondria by added 3'-azido-3'-deoxythymidine.

    PubMed

    Valenti, D; Barile, M; Quagliariello, E; Passarella, S

    1999-02-12

    The effect of 3'-azido-3'-deoxythymidine on nucleoside diphosphate kinase of isolated rat liver mitochondria has been studied. This is done by monitoring the increase in the rate of oxygen uptake by nucleoside diphosphate (TDP, UDP, CDP or GDP) addition to mitochondria in state 4. It is shown that 3'-azido-3'-deoxythymidine inhibits the mitochondrial nucleoside diphosphate kinase in a competitive manner, with a Ki value of about 10 microM as measured for each tested nucleoside diphosphate. It is also shown that high concentrations of GDP prevent 3'-azido-3'-deoxythymidine inhibition of the nucleoside diphosphate kinase. PMID:10050777

  14. Anomalous Reactivity and Selectivity in the Intermolecular Diels-Alder Reactions of Multisubstituted Acyclic Dienes with Geometrical Isomers of Enals.

    PubMed

    Zhou, Jia-Hui; Cai, Sai-Hu; Xu, Yun-He; Loh, Teck-Peng

    2016-05-20

    A Lewis-acid catalyzed intermolecular Diels-Alder reaction between multisubstituted acyclic dienes and the E and Z isomers of α,β-enals was studied. It was found that the diene reacted selectively with the Z-isomer of the α,β-enal. PMID:27132468

  15. Incorporation of Phosphonate into Benzonaphthyridine Toll-like Receptor 7 Agonists for Adsorption to Aluminum Hydroxide.

    PubMed

    Cortez, Alex; Li, Yongkai; Miller, Andrew T; Zhang, Xiaoyue; Yue, Kathy; Maginnis, Jillian; Hampton, Janice; Hall, De Shon; Shapiro, Michael; Nayak, Bishnu; D'Oro, Ugo; Li, Chun; Skibinski, David; Mbow, M Lamine; Singh, Manmohan; O'Hagan, Derek T; Cooke, Michael P; Valiante, Nicholas M; Wu, Tom Y-H

    2016-06-23

    Small molecule Toll-like receptor 7 (TLR7) agonists have been used as vaccine adjuvants by enhancing innate immune activation to afford better adaptive response. Localized TLR7 agonists without systemic exposure can afford good adjuvanticity, suggesting peripheral innate activation (non-antigen-specific) is not required for immune priming. To enhance colocalization of antigen and adjuvant, benzonaphthyridine (BZN) TLR7 agonists are chemically modified with phosphonates to allow adsorption onto aluminum hydroxide (alum), a formulation commonly used in vaccines for antigen stabilization and injection site deposition. The adsorption process is facilitated by enhancing aqueous solubility of BZN analogs to avoid physical mixture of two insoluble particulates. These BZN-phosphonates are highly adsorbed onto alum, which significantly reduced systemic exposure and increased local retention post injection. This report demonstrates a novel approach in vaccine adjuvant design using phosphonate modification to afford adsorption of small molecule immune potentiator (SMIP) onto alum, thereby enhancing co-delivery with antigen. PMID:27270029

  16. Role of Purine Nucleoside Phosphorylase in Interactions between 2′,3′-Dideoxyinosine and Allopurinol, Ganciclovir, or Tenofovir

    PubMed Central

    Ray, Adrian S.; Olson, Loren; Fridland, Arnold

    2004-01-01

    The level of systemic exposure to 2′,3′-dideoxyinosine (ddI) is increased 40 to 300% when it is coadministered with allopurinol (Allo), ganciclovir (GCV), or tenofovir. However, the mechanism for these drug interactions remains undefined. A metabolic route for ddI clearance is its breakdown by purine nucleoside phosphorylase (PNP). Consistent with previous reports, enzymatic inhibition assays showed that acyclic nucleotide analogs can inhibit the phosphorolysis of inosine. It was further established that the mono- and diphosphate forms of tenofovir were inhibitors of PNP-dependent degradation of ddI (Kis, 38 nM and 1.3 μM, respectively). Allo and its metabolites were found to be relatively weak inhibitors of PNP (Kis, >100 μM). Coadministration of tenofovir, GCV, or Allo decreased the amounts of intracellular ddI breakdown products in CEM cells, while they increased the ddI concentrations (twofold increase with each drug at approximately 20 μM). While inhibition of the physiological function of PNP is unlikely due to the ubiquitous presence of high levels of enzymatic activity, phosphorylated metabolites of GCV and tenofovir may cause the increased level of exposure to ddI by direct inhibition of its phosphorolysis by PNP. The discrepancy between the cellular activity of Allo and the weak enzyme inhibition by Allo and its metabolites may be explained by an indirect mechanism of PNP inhibition. This mechanism may be facilitated by the unfavorable equilibrium of PNP and the buildup of one of its products (hypoxanthine) through the inhibition of xanthine oxidase by Allo. These findings support the inhibition of PNP-dependent ddI degradation as the molecular mechanism of these drug interactions. PMID:15047506

  17. Resistance of human immunodeficiency virus type 1 to acyclic 6-phenylselenenyl- and 6-phenylthiopyrimidines.

    PubMed Central

    Nguyen, M H; Schinazi, R F; Shi, C; Goudgaon, N M; McKenna, P M; Mellors, J W

    1994-01-01

    Acyclic 6-phenylselenenyl- and 6-phenylthiopyrimidine derivatives are potent and specific inhibitors of human immunodeficiency virus type 1 (HIV-1). The development of in vitro resistance to two derivatives, 5-ethyl-1-(ethoxymethyl)-(6-phenylthio)-uracil (E-EPU), was evaluated by serial passage of HIV-1 in increasing concentrations of inhibitor. HIV-1 variants exhibiting > 500-fold resistance to E-EPSeU and E-EPU were isolated after sequential passage in 1, 5, and 10 microM inhibitor. The resistant variants exhibited coresistance to related acyclic 6-substituted pyrimidines and the HIV-1-specific inhibitors (+)-(5S)-4,5,6,7-tetrahydro-5- pyrimidines and the HIV-1-specific inhibitors (+)-(5S)-4,5,6,7-tetrahydro-5- methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk]benzodiazepin-2(1H)- thione (TIBO R82150) and nevirapine, but remained susceptible to 3'-azido-3'-deoxythymidine, 2',3'-dideoxycytidine, 2',3'-dideoxyinosine, and phosphonoformic acid. DNA sequence analysis of reverse transcriptase (RT) derived from E-EPSeU-resistant virus identified a Tyr (TAT)-to-Cys (TGT) mutation at either codon 188 (Cys-188; 9 of 15 clones) or codon 181 (Cys-181; 5 of 15 clones). The same amino acid changes were found in RT from E-EPU-resistant virus, but the Cys-181 mutation was more common (9 of 10 clones) than the Cys-188 mutation (1 of 10 clones). Site-specific mutagenesis and production of mutant recombinant viruses demonstrated that both the Cys-181 and Cys-188 mutations cause resistance to E-EPSeU and E-EPU. Of the two mutations, the Cys-188 substitution produced greater E-EPSeU and E-EPU resistance. The predominance of the Cys-188 mutation in E-EPSeU-resistant variants has not been noted for other classes of HIV-1 specific RT inhibitors. HIV-1 resistance is likely to limit the therapeutic efficacy of acyclic 6-substituted pyrimidines if they are used as monotherapy. PMID:7840579

  18. The GABA transaminase, ABAT, is essential for mitochondrial nucleoside metabolism

    PubMed Central

    Besse, Arnaud; Wu, Ping; Bruni, Francesco; Donti, Taraka; Graham, Brett H.; Craigen, William J.; McFarland, Robert; Moretti, Paolo; Lalani, Seema; Scott, Kenneth L.; Taylor, Robert W.; Bonnen, Penelope E.

    2015-01-01

    Summary ABAT is a key enzyme responsible for catabolism of principal inhibitory neurotransmitter gamma-aminobutyric acid (GABA). We report an essential role for ABAT in a seemingly unrelated pathway, mitochondrial nucleoside salvage, and demonstrate that mutations in this enzyme cause an autosomal recessive neurometabolic disorder and mtDNA depletion syndrome (MDS). We describe a family with encephalomyopathic MDS caused by a homozygous missense mutation in ABAT that results in elevated GABA in subjects’ brains as well as decreased mtDNA levels in subjects’ fibroblasts. Nucleoside rescue and co-IP experiments pinpoint that ABAT functions in the mitochondrial nucleoside salvage pathway to facilitate conversion of dNDPs to dNTPs. Pharmacological inhibition of ABAT through the irreversible inhibitor Vigabatrin caused depletion of mtDNA in photoreceptor cells that was prevented through addition of dNTPs in cell culture media. This work reveals ABAT as a connection between GABA metabolism and nucleoside metabolism and defines a neurometabolic disorder that includes MDS. PMID:25738457

  19. Macrophages require different nucleoside transport systems for proliferation and activation.

    PubMed

    Soler, C; García-Manteiga, J; Valdés, R; Xaus, J; Comalada, M; Casado, F J; Pastor-Anglada, M; Celada, A; Felipe, A

    2001-09-01

    To evaluate the mechanisms involved in macrophage proliferation and activation, we studied the regulation of the nucleoside transport systems. In murine bone marrow-derived macrophages, the nucleosides required for DNA and RNA synthesis are recruited from the extracellular medium. M-CSF induced macrophage proliferation and DNA and RNA synthesis, whereas interferon gamma (IFN-gamma) led to activation, blocked proliferation, and induced only RNA synthesis. Macrophages express at least the concentrative systems N1 and N2 (CNT2 and CNT1 genes, respectively) and the equilibrative systems es and ei (ENT1 and ENT2 genes, respectively). Incubation with M-CSF only up-regulated the equilibrative system es. Inhibition of this transport system blocked M-CSF-dependent proliferation. Treatment with IFN-gamma only induced the concentrative N1 and N2 systems. IFN-gamma also down-regulated the increased expression of the es equilibrative system induced by M-CSF. Thus, macrophage proliferation and activation require selective regulation of nucleoside transporters and may respond to specific requirements for DNA and RNA synthesis. This report also shows that the nucleoside transporters are critical for macrophage proliferation and activation. PMID:11532978

  20. Arabidopsis thaliana nucleosidase mutants provide new insights into nucleoside degradation

    PubMed Central

    Riegler, Heike; Geserick, Claudia; Zrenner, Rita

    2011-01-01

    A central step in nucleoside and nucleobase salvage pathways is the hydrolysis of nucleosides to their respective nucleobases. In plants this is solely accomplished by nucleosidases (EC 3.2.2.x). To elucidate the importance of nucleosidases for nucleoside degradation, general metabolism, and plant growth, thorough phenotypic and biochemical analyses were performed using Arabidopsis thaliana T-DNA insertion mutants lacking expression of the previously identified genes annotated as uridine ribohydrolases (URH1 and URH2). Comprehensive functional analyses of single and double mutants demonstrated that both isoforms are unimportant for seedling establishment and plant growth, while one participates in uridine degradation. Rather unexpectedly, nucleoside and nucleotide profiling and nucleosidase activity screening of soluble crude extracts revealed a deficiency of xanthosine and inosine hydrolysis in the single mutants, with substantial accumulation of xanthosine in one of them. Mixing of the two mutant extracts, and by in vitro activity reconstitution using a mixture of recombinant URH1 and URH2 proteins, both restored activity, thus providing biochemical evidence that at least these two isoforms are needed for inosine and xanthosine hydrolysis. This mutant study demonstrates the utility of in vivo systems for the examination of metabolic activities, with the discovery of the new substrate xanthosine and elucidation of a mechanism for expanding the nucleosidase substrate spectrum. PMID:21599668

  1. Nucleoside-Based Diarylethene Photoswitches: Synthesis and Photochromic Properties.

    PubMed

    Wang, Hai-Xia; Xi, Dan-Dan; Xie, Ming-Sheng; Wang, Hui-Xuan; Qu, Gui-Rong; Guo, Hai-Ming

    2016-07-01

    Diarylethene photoswitches based on the natural nucleoside deoxyadenosine were designed and synthesized. In aqueous solution, some of them exhibited good photochromic properties, including clear changes in color upon irradiation at 365 nm, red-shifts of the absorption wavelength, with good fatigue resistance, thermal stability, conversion efficiency, and base-pairing properties. PMID:27124421

  2. Theophylline inhibition of renal and cerebral nucleoside formation.

    PubMed Central

    Jensen, M. H.

    1981-01-01

    1 Theophylline inhibits the enzymatic formation of purine nucleosides, among these adenosine (dephosphorylated adenosine 5'-monophosphate), in kidney and brain of the rat. 2 Some pharmacological effects of theophylline on regional blood flow and electrophysiological activity of the nervous system may be caused by inhibition of the endogenous formation of adenosine. PMID:7236996

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

    PubMed

    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

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

    SciTech Connect

    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.

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

    PubMed

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

    2016-10-14

    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. PMID:27608753

  6. Atypical temperature-dependence of symmetry transformation observed in a uranyl phosphonate.

    PubMed

    Zheng, Tao; Gao, Yang; Gui, Daxiang; Chen, Lanhua; Sheng, Daopeng; Diwu, Juan; Chai, Zhifang; Albrecht-Schmitt, Thomas E; Wang, Shuao

    2016-05-31

    The example of phase transformation from a centrosymmetric space group at low temperature (LT) to a chiral space group at high temperature (HT) is reported, which was clearly resolved in a single-crystal-to-single-crystal manner in a 3D uranyl(vi) phosphonate compound [TMA][(UO2)2(1,3-pbpH)(1,3-pbpH2)] () (TMA(+) = tetramethylammonium cation; 1,3-pbpH4 = 1,3-phenylenebis(phosphonic acid)). PMID:27184289

  7. Design of a humidity-stable metal-organic framework using a phosphonate monoester ligand.

    PubMed

    Gelfand, Benjamin S; Lin, Jian-Bin; Shimizu, George K H

    2015-02-16

    Phosphonate monoesters are atypical linkers for metal-organic frameworks, but they offer potentially added versatility. In this work, a bulky isopropyl ester is used to direct the topology of a copper(II) network from a dense to an open framework, CALF-30. CALF-30 shows no adsorption of N2 or CH4 however, using CO2 sorption, CALF-30 was found to have a Langmuir surface area of over 300 m(2)/g and to be stable to conditions of 90% relative humidity at 353 K owing to kinetic shielding of the framework by the phosphonate ester. PMID:25646642

  8. Unsaturated Phosphonates as Hauser Acceptors for the Synthesis of Phosphonylated Dihydroxynaphthalenes and Naphthoquinones.

    PubMed

    Chaturvedi, Atul Kumar; Rastogi, Namrata

    2016-04-15

    The unsaturated phosphonates were utilized as Hauser acceptors successfully for the first time. The products phosphonylated 1,4-dihydroxynaphthalenes were isolated in good yields in short reaction time and were further oxidized to the corresponding 1,4-naphthoquinones in quantitative yields. The reaction provides an efficient and straightforward approach for the synthesis of pharmacologically privileged disubstituted naphthalene-1,4-diols and naphtha-1,4-diones bearing a phosphonate group at the 2-position and various (het)aryl groups at the 3-position. PMID:27049927

  9. Microbial transformations in phosphonate biosynthesis and catabolism, and their importance in nutrient cycling.

    PubMed

    Chin, Jason P; McGrath, John W; Quinn, John P

    2016-04-01

    Phosphorus cycling in the biosphere has traditionally been thought to involve almost exclusively transformations of the element in its pentavalent oxidation state. Recent evidence, however, suggests that a significant fraction of environmental phosphorus may exist in a more reduced form. Most abundant of these reduced phosphorus compounds are the phosphonates, with their direct carbon-phosphorus bonds, and striking progress has recently been made in elucidating the biochemistry of microbial phosphonate transformations. These advances are now presented in the context of their contribution to our understanding of phosphorus biogeochemistry and of such diverse fields as the productivity of the oceans, marine methanogenesis and the discovery of novel microbial antimetabolites. PMID:26836350

  10. Selective loss of nucleoside carrier expression in rat hepatocarcinomas.

    PubMed

    Dragan, Y; Valdés, R; Gomez-Angelats, M; Felipe, A; Javier Casado, F; Pitot, H; Pastor-Anglada, M

    2000-08-01

    Evidence that hepatoma cell lines show differential expression of concentrative nucleoside transporters (CNT1 and CNT2) prompted us to study the transporter proteins in 2 models of hepatocarcinogenesis, the chemically induced Solt and Farber model and the albumin-SV40 large T antigen (Alb-SV40) transgenic rat. CNT1 expression was lower in tumor biopsy specimens from Alb-SV40 rat livers than in normal tissue. Immunocytochemistry revealed that the CNT1 protein was indeed absent in the tumor lesions. CNT1 was also absent in a cell line, L25, derived from the Alb-SV40 transgenic rat liver tumors, whereas another cell line, L37, derived from the normal-appearing parenchyma, retained the expression of both carrier isoforms. The protein expression correlated with the nucleoside transport properties of these cell lines. Moreover, although CNT2 expression was highly dependent on the growth characteristics of the 2 cell lines, as was CNT1 (albeit to a lower extent) in L37 cells, it was not expressed in L25 cells at any stage of cell growth. In contrast to the transgenic model of hepatocarcinogenesis, in the chemically induced tumors the expression of CNT2 was lower, although still detectable. In summary, these data indicate that hepatocarcinogenesis leads to a selective loss or diminished expression of nucleoside carrier isoforms, a feature that may be relevant to our understanding of the molecular basis of the bioavailability of those drugs that are nucleoside derivatives and may be substrates of these carriers. The transport properties and isoform-expression profile of the L25 and L37 cell lines make them suitable hepatocyte culture models with which to study nucleoside transport processes and drug sensitivity. PMID:10915730

  11. Sensing Metal Ions with DNA Building Blocks: Fluorescent Pyridobenzimidazole Nucleosides

    PubMed Central

    Kim, Su Jeong; Kool, Eric T.

    2008-01-01

    We describe novel fluorescent N-deoxyribosides (1 and 2) having 2-pyrido-2-benzimidazole and 2-quino-2-benzimidazole as aglycones. The compounds were prepared from the previously unknown heterocyclic precursors and Hoffer’s chlorosugar, yielding alpha anomers as the chief products. X-ray crystal structures confirmed the geometry, and showed that the pyridine and benzimidazole ring systems deviated from coplanarity in the solid state by 154° and 140°, respectively. In methanol the compounds 1 and 2 had absorption maxima at 360 and 370 nm respectively, and emission maxima at 494 and 539 nm. Experiments revealed varied fluorescence responses of the nucleosides to a panel of seventeen monovalent, divalent and trivalent metal ions in methanol. One or both of the nucleosides showed significant changes with ten of the metal ions. The most pronounced spectral changes for ligand-nucleoside 1 included red shifts in fluorescence (Au+, Au3+), strong quenching (Cu2+, Ni2+, Pt2+), and in substantial enhancements in emission intensity coupled with redshifts (Ag+, Cd2+, Zn2+). The greatest spectral changes for ligand-nucleoside 2 included a redshift in fluorescence (Ag+), a blueshift (Cd2+), strong quenching (Pd2+, Pt2+), and in substantial enhancements in emission intensity coupled with a blueshift (Zn2+). The compounds could be readily incorporated into oligodeoxynucleotides, where an initial study revealed that they retained sensitivity to metal ions in aqueous solution, and demonstrated possible cooperative sensing behavior with several ions. The two free nucleosides alone can act as differential sensors for at multiple metal ions, and they are potentially useful monomers for contributing metal ion sensing capability to DNAs. PMID:16669686

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

    PubMed

    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

  13. The Acyclic Retinoid Peretinoin Inhibits Hepatitis C Virus Replication and Infectious Virus Release in Vitro

    NASA Astrophysics Data System (ADS)

    Shimakami, Tetsuro; Honda, Masao; Shirasaki, Takayoshi; Takabatake, Riuta; Liu, Fanwei; Murai, Kazuhisa; Shiomoto, Takayuki; Funaki, Masaya; Yamane, Daisuke; Murakami, Seishi; Lemon, Stanley M.; Kaneko, Shuichi

    2014-04-01

    Clinical studies suggest that the oral acyclic retinoid Peretinoin may reduce the recurrence of hepatocellular carcinoma (HCC) following surgical ablation of primary tumours. Since hepatitis C virus (HCV) infection is a major cause of HCC, we assessed whether Peretinoin and other retinoids have any effect on HCV infection. For this purpose, we measured the effects of several retinoids on the replication of genotype 1a, 1b, and 2a HCV in vitro. Peretinoin inhibited RNA replication for all genotypes and showed the strongest antiviral effect among the retinoids tested. Furthermore, it reduced infectious virus release by 80-90% without affecting virus assembly. These effects could be due to reduced signalling from lipid droplets, triglyceride abundance, and the expression of mature sterol regulatory element-binding protein 1c and fatty acid synthase. These negative effects of Peretinoin on HCV infection may be beneficial in addition to its potential for HCC chemoprevention in HCV-infected patients.

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

    PubMed

    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

  15. Halogen bonding in water results in enhanced anion recognition in acyclic and rotaxane hosts.

    PubMed

    Langton, Matthew J; Robinson, Sean W; Marques, Igor; Félix, Vítor; Beer, Paul D

    2014-12-01

    Halogen bonding (XB), the attractive interaction between an electron-deficient halogen atom and a Lewis base, has undergone a dramatic development as an intermolecular force analogous to hydrogen bonding (HB). However, its utilization in the solution phase remains underdeveloped. Furthermore, the design of receptors capable of strong and selective recognition of anions in water remains a significant challenge. Here we demonstrate the superiority of halogen bonding over hydrogen bonding for strong anion binding in water, to the extent that halide recognition by a simple acyclic mono-charged receptor is achievable. Quantification of iodide binding by rotaxane hosts reveals the strong binding by the XB-rotaxane is driven exclusively by favourable enthalpic contributions arising from the halogen-bonding interactions, whereas weaker association with the HB-rotaxanes is entropically driven. These observations demonstrate the unique nature of halogen bonding in water as a strong alternative interaction to the ubiquitous hydrogen bonding in molecular recognition and assembly. PMID:25411880

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

    PubMed Central

    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

  17. Acyclic N-halamine-immobilized polyurethane: Preparation and antimicrobial and biofilm-controlling functions

    PubMed Central

    Luo, Jie; Porteous, Nuala; Lin, Jiajin; Sun, Yuyu

    2015-01-01

    Hydroxyl groups were introduced onto polyurethane surfaces through 1,6-hexamethylene diisocyanate activation, followed by diethanolamine hydroxylation. Polymethacrylamide was covalently attached to the hydroxylated polyurethane through surface grafting polymerization of methacrylamide using cerium (IV) ammonium nitrate as an initiator. After bleach treatment, the amide groups of the covalently bound polymethacrylamide chains were transformed into N-halamines. The new N-halamine-immobilized polyurethane provided a total sacrifice of 107–108 colony forming units per milliliter of Staphylococcus aureus (Gram-positive bacteria), Escherichia coli (Gram-negative bacteria), and Candida albicans (fungi) within 10 min and successfully prevented bacterial and fungal biofilm formation. The antimicrobial and biofilm-controlling effects were both durable and rechargeable, pointing to great potentials of the new acyclic N-halamine-immobilized polyurethane for a broad range of related applications. PMID:26089593

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

    PubMed Central

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

    2014-01-01

    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. PMID:25195883

  19. A New Subfamily of Polyphosphate Kinase 2 (Class III PPK2) Catalyzes both Nucleoside Monophosphate Phosphorylation and Nucleoside Diphosphate Phosphorylation

    PubMed Central

    Motomura, Kei; Hirota, Ryuichi; Okada, Mai; Ikeda, Takeshi; Ishida, Takenori

    2014-01-01

    Inorganic polyphosphate (polyP) is a linear polymer of tens to hundreds of phosphate (Pi) residues linked by “high-energy” phosphoanhydride bonds as in ATP. PolyP kinases, responsible for the synthesis and utilization of polyP, are divided into two families (PPK1 and PPK2) due to differences in amino acid sequence and kinetic properties. PPK2 catalyzes preferentially polyP-driven nucleotide phosphorylation (utilization of polyP), which is important for the survival of microbial cells under conditions of stress or pathogenesis. Phylogenetic analysis suggested that the PPK2 family could be divided into three subfamilies (classes I, II, and III). Class I and II PPK2s catalyze nucleoside diphosphate and nucleoside monophosphate phosphorylation, respectively. Here, we demonstrated that class III PPK2 catalyzes both nucleoside monophosphate and nucleoside diphosphate phosphorylation, thereby enabling us to synthesize ATP from AMP by a single enzyme. Moreover, class III PPK2 showed broad substrate specificity over purine and pyrimidine bases. This is the first demonstration that class III PPK2 possesses both class I and II activities. PMID:24532069

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

    PubMed

    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. PMID:25195883

  1. Acyclic hydrocarbon environments ⩾ n-C 18 on the early terrestrial planets

    NASA Astrophysics Data System (ADS)

    Marcano, Vicente; Benitez, Pedro; Palacios-Prü, Ernesto

    2003-03-01

    The possible occurrence on the surface of the early Earth, Mars and Venus of hydrocarbon environments mainly composed by acyclic alkane molecules ⩾ n-C 18 has been revised. These hydrocarbons could be accumulated from the contribution of endogenous Fischer-Tropsh-type reactions and post-impact recombination reactions, as well as from exogenous sources such as comets, meteorites and dust particles. Such heavy alkane environments could offer protection for the synthesis and survival of biomolecules on the early terrestrial planets. Amounts of heavy n-alkanes delivered by large impactors, dust particles or produced by post-impact recombination on Venus would have been higher than those delivered or produced by the same sources on Earth and Mars before 3600 Myr ago. However, the high values of the total frequency of impacts by bolides >14-km in diameter estimated in this time period (viz. 3.9×10 3, Mars; 2.2×10 4, Earth, and 3.8×10 4 Venus) and the high surface temperatures generated by those impactors suggest the existence of very unstable conditions on the early terrestrial planets for the survival and long-term accumulation of acyclic hydrocarbons. Therefore, the most significant accumulation of n-alkanes could have occurred only during the longer intervals (10 5- 10 7 yr) between each impact through the contribution mainly of IDPs, and thereby a high decomposition rate would be expected for the accumulated n-alkanes by successive impacts. Amounts of n-alkanes accumulated from IDPs in these intervals have been estimated between 2.3×10 9 and 2.2×10 10 kg 3600- 3800 Myr ago. These processes are expected to occur on other planetary bodies or satellites belonging to our solar system and probably in analogs of the early solar system.

  2. Nucleoside transporters, bcl-2 and apoptosis in CLL cells exposed to nucleoside analogues in vitro.

    PubMed

    Petersen, A J; Brown, R D; Gibson, J; Pope, B; Luo, X F; Schutz, L; Wiley, J S; Joshua, D E

    1996-04-01

    The purine nucleoside analogues fludarabine (F1) and chlorodeoxyadenosine (2-CdA) are considered to be cell cycle specific agents which require DNA synthesis for cytotoxicity. However, their efficacy in the treatment of CLL, an indolent lymphoid malignancy suggests additional mechanisms of action. Like cytosine arabinoside (AraC), F1 and 2-CdA gain access to the cell via a specific nucleoside transporter (NST) protein. To investigate the mode of action of these drugs in CLL, we used a fluorescent ligand for the NST (5'-(SAENTA- x8)-fluorescein) and 3-colour flow cytometry to determine NST expression on CD5+/CD19+ B-cells from the peripheral blood (PB) of patients with CLL. NST levels on these cells was found to be not significantly different from normal control lymphocytes (mean = 485 +/- 425) vs. (mean = 553 +/- 178). Exposure to varying concentrations (0, 3 microM and 30 microM) of F1 and 2-CdA, however, resulted in an upregulation of NST (mean = 1552 +/- 775 with 30 microM FL; mean = 3392 +/- 2197 with 30 microM 2-CdA) after 48. "Large" lymphoid cells (not present in normal PB) were found to express significantly more NST (mean = 2540 +/- 2861) and have a higher proliferative capacity than "small" cells (mean = 357 +/- 517 NST/cell). Incubation of CLL cells with F1 (n = 6) and 2-CdA (n = 8) in vitro over 48 h also resulted in an increase in the proportion of cells in S-phase (0 microM = 0.2 + 2 - 0.1; 30 microM FL = 2.4 +/- 2.0; 30 microM 2-CdA = 3.3 +/- 1.3) and a significant increase in morphologically identifiable apoptosis. Apoptosis was confirmed by flow cytometric DNA analysis (0 microM = 13 +/- 8%; 30 microM FL = 40 +/- 20%; 30 microM 2-CdA = 48 +/- 11%). In situ hybridization using a biotinylated cDNA bcl-2 probe demonstrated that bcl-2 mRNA expression was markedly decreased in treated cells after 24 h. These studies have demonstrated that: (1) NST expression on CLL lymphocytes is low; (2) in vitro exposure to the analogues increases both the level of

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

    PubMed

    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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  5. A diethyl phosphonate containing oxazoline: Synthesis and characterization of monomer and homopolymer

    SciTech Connect

    Hermes, R.E.; Thompson, R.D.; Valdez, L.S.

    1995-05-01

    A diethyl phosphonate oxazoline monomer and its polymer have been synthesized. The monomer appears to polymerize via a ring-opening mechanism giving the expected polyethyleneimine backbone with pendant carbonyl groups. Two distinct molecular weights were produced during polymerization suggesting two mechanisms of chain growth. Studies are underway to elucidate the reasons for this. This polymer has potential as a metal-chelating agent.

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

    SciTech Connect

    Laskowski, Lukasz; Laskowska, Magdalena

    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.

  7. 40 CFR 721.6075 - Phosphonic acid, 1,1-methylenebis-tetrakis(1-methylethyl) ester.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... substance identified as phosphonic acid, 1,1-methylenebis-tetrakis(1-methylethyl) ester (PMN P-95-168) is... paragraph. (1) Recordkeeping. Recordkeeping requirements as specified in § 721.125 (a) through (h) are... AGENCY (CONTINUED) TOXIC SUBSTANCES CONTROL ACT SIGNIFICANT NEW USES OF CHEMICAL SUBSTANCES...

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

    PubMed

    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

  9. Evaluation of phosphonate treatments for control of phytophthora crown rot of walnut

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Foliar and soil applications of phosphonate were evaluated in a factorial manner for control of trunk cankers caused by Phytophthora citricola in a Persian walnut orchard, cultivar ‘Chandler’. In each of two experiments, the foliar treatment was applied once in the second week of September, whereas...

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

    PubMed Central

    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. Seasonal Expression of the Picocyanobacterial Phosphonate Transporter Gene phnD in the Sargasso Sea.

    PubMed

    Ilikchyan, Irina N; McKay, Robert Michael L; Kutovaya, Olga A; Condon, Rob; Bullerjahn, George S

    2010-01-01

    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. PMID:21687717

  12. Hydrothermal synthesis and structural characterization of ammonium ion-templated lanthanide(III) carboxylate-phosphonates

    PubMed Central

    Ayi, Ayi A.; Kinnibrugh, Tiffany L.; Clearfield, Abraham

    2014-01-01

    Using N-(phosphonomethyl) iminodiacetic acid (H4PMIDA), as a complexing agent, two new complexes, (NH4)La(PMIDA)(H2O)•H2O, 1 and (NH4)Yb(PMIDA), 2 have been synthesized hydrothermally. In both compounds, the metal ions are trapped by a three five-membered chelate rings by the chelating PMIDA anions giving a tricapped trigonal prismatic LaO8N and monocapped trigonal prismatic YbO6N geometries for 1 and 2, respectively. The structure of 1 consists of La(PMIDA)(H2O) chelating units, linked together by the phosphonate oxygen atoms O1 and O3 to form a chain along the c-axis. The chains are then connected together by the bridging phosphonate oxygen O2 to form a 2D layered structure with alternating 4- and 8-membered apertures. The structure of 2 consists Yb(PMIDA) chelating units, which are connected by alternating bridging carboxylate and phosphonate groups along the [010] direction forming chains with a corrugated pattern. The third phosphonate oxygen bridges the chains together along the [001] direction to build the two-dimensional layer with 4- and 6-membered apertures in the bc-plane. Under excitation of 330 nm, compound 2 shows a broad emission band at λmax = 460 nm. This emission is essentially in the blue luminescent region, which corresponds to ligand centered fluorescence. PMID:25414845

  13. Hydrogen-Bond Basic Siloxane Phosphonate Polymers for Surface Acoustic Wave (Saw) Sensors

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A surface acoustic wave (SAW) sensor coated with a novel hydrogen-bond basic siloxane phosphonate SAW polymer gave excellent initial response and long-term performance when tested against phenol vapor and compared with polyethyleneimine (PEI), a conventional hydrogent-bond basic SAW polymer....

  14. Thermal decomposition reactions of cotton fabric treated with piperazine-phosphonates derivatives as a flame retardant

    Technology Transfer Automated Retrieval System (TEKTRAN)

    There has been a great scientific interest in exploring the great potential of the piperazine-phosphonates in flame retardant (FR) application on cotton fabric by investigating the thermal decomposition of cotton fabric treated with them. This research tries to understand the mode of action of the t...

  15. Investigation of the extraction properties of dibutyl ester of dibutoxymethane phosphonic acid

    SciTech Connect

    Herrmann, E.; Hala, J.

    1983-01-01

    The extraction properties of the dibutyl ester of dibutoxymethane phosphonic acid (DBDBMP), an analog of TBP with a P-C bond, were shown to be similar to those of TBP except for hydrolysis of DBDBMP in acidic solutions. The formation of acidic organophosphorus compounds during hydrolysis of DBDBMP was confirmed by /sup 31/P-N.M.R. measurements. 4 figures, 1 table.

  16. Synthesis of homo and hetero metal-phosphonate frameworks from bi-functional aminomethylphosphonic acid

    SciTech Connect

    Samanamu, Christian R.; Zamora, Elena Nicole; Montchamp, Jean-Luc; Richards, Anne F.

    2008-06-15

    The reaction between aminomethylphosphonic acid (ampa) and the metal salts of Zn, Cd, Hg, Pb, Ag, and Cu afforded seven metal-phosphonate polymers with unique structural features and includes the synthesis of a bimetallic metal-organic framework (Cu/Ag). The characterization of these metal phosphonates is reported by means of infrared spectroscopy, {sup 1}H-NMR, {sup 31}P-NMR, X-ray crystallography, energy dispersive X-ray (EDX), and thermogravimetric analysis (TGA). Individual structural features are compared based on the preferred coordination mode of ampa and the geometrical requirements for each metallic center that manipulates the structural motif. - Graphical abstract: The synthesis and characterization of polymeric metal phosphonates featuring zinc, cadmium, mercury, lead, and silver phosphonate are described from the reactions of the bi-funtional aminomethylphosphonic acid with the metal precursor in aqueous conditions. These previously undescribed polymers display unusual structural features and include the synthesis of a bimetallic metal-organic framework (Cu/Ag)

  17. Comparison of Zirconium Phosphonate-Modified Surfaces for Immobilizing Phosphopeptides and Phosphate-Tagged Proteins.

    PubMed

    Forato, Florian; Liu, Hao; Benoit, Roland; Fayon, Franck; Charlier, Cathy; Fateh, Amina; Defontaine, Alain; Tellier, Charles; Talham, Daniel R; Queffélec, Clémence; Bujoli, Bruno

    2016-06-01

    Different routes for preparing zirconium phosphonate-modified surfaces for immobilizing biomolecular probes are compared. Two chemical-modification approaches were explored to form self-assembled monolayers on commercially available primary amine-functionalized slides, and the resulting surfaces were compared to well-characterized zirconium phosphonate monolayer-modified supports prepared using Langmuir-Blodgett methods. When using POCl3 as the amine phosphorylating agent followed by treatment with zirconyl chloride, the result was not a zirconium-phosphonate monolayer, as commonly assumed in the literature, but rather the process gives adsorbed zirconium oxide/hydroxide species and to a lower extent adsorbed zirconium phosphate and/or phosphonate. Reactions giving rise to these products were modeled in homogeneous-phase studies. Nevertheless, each of the three modified surfaces effectively immobilized phosphopeptides and phosphopeptide tags fused to an affinity protein. Unexpectedly, the zirconium oxide/hydroxide modified surface, formed by treating the amine-coated slides with POCl3/Zr(4+), afforded better immobilization of the peptides and proteins and efficient capture of their targets. PMID:27166821

  18. 40 CFR 721.6075 - Phosphonic acid, 1,1-methylenebis-tetrakis(1-methylethyl) ester.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ...-tetrakis(1-methylethyl) ester. 721.6075 Section 721.6075 Protection of Environment ENVIRONMENTAL PROTECTION...-methylethyl) ester. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as phosphonic acid, 1,1-methylenebis-tetrakis(1-methylethyl) ester (PMN P-95-168)...

  19. 40 CFR 721.6075 - Phosphonic acid, 1,1-methylenebis-tetrakis(1-methylethyl) ester.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ...-tetrakis(1-methylethyl) ester. 721.6075 Section 721.6075 Protection of Environment ENVIRONMENTAL PROTECTION...-methylethyl) ester. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as phosphonic acid, 1,1-methylenebis-tetrakis(1-methylethyl) ester (PMN P-95-168)...

  20. 40 CFR 721.10412 - Phosphonic acid ester (generic) (P-07-706).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... appropriate gas/vapor cartridges (organic vapor, acid gas, or substance-specific); NIOSH-certified powered air... (organic vapor, acid gas, or substance-specific); NIOSH-certified powered air-purifying respirator with a... Specific Chemical Substances § 721.10412 Phosphonic acid ester (generic) (P-07-706). (a) Chemical...

  1. 40 CFR 721.10412 - Phosphonic acid ester (generic) (P-07-706).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... appropriate gas/vapor cartridges (organic vapor, acid gas, or substance-specific); NIOSH-certified powered air... (organic vapor, acid gas, or substance-specific); NIOSH-certified powered air-purifying respirator with a... Specific Chemical Substances § 721.10412 Phosphonic acid ester (generic) (P-07-706). (a) Chemical...

  2. 40 CFR 721.10412 - Phosphonic acid ester (generic) (P-07-706).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... appropriate gas/vapor cartridges (organic vapor, acid gas, or substance-specific); NIOSH-certified powered air... (organic vapor, acid gas, or substance-specific); NIOSH-certified powered air-purifying respirator with a... Specific Chemical Substances § 721.10412 Phosphonic acid ester (generic) (P-07-706). (a) Chemical...

  3. The mechanism of action of piperazine-phosphonates derivatives in cotton fabric

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Piperazine-phosphonates additives are known to be very effective flame retardants on different polymeric systems, especially cotton cellulose. In order to understand their mechanism of action, we carried out the investigation of their thermal behavior on cotton fabric by, first, employing the attenu...

  4. Multifunctional water-soluble molecular capsules based on p-phosphonic acid calix[5]arene.

    PubMed

    Martin, Adam D; Boulos, Ramiz A; Hubble, Lee J; Hartlieb, Karel J; Raston, Colin L

    2011-07-14

    p-Phosphonic acid calix[5]arene forms molecular capsules in water based on two of the molecules, which can be loaded with carboplatin using intense shearing, and attached to single wall carbon nano-tubes. Spin coating of the capsules onto a substrate affords 2 nm fibres of stacked calixarenes, with the self-assembly understood using molecular modelling. PMID:21637889

  5. Flame Resistant Cotton Durability and Antimicrobial Resistance Properties by using a Novel Epoxy Phosphonate Monomers

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Recently we showed the design, synthesis, characterization, and usefulness of 2-(dimethoxy-phosphorylmethyl)-oxiranylmethyl]-phosphonic acid dimethyl ester that was generated from 3-chloro-2-chloromethylpropene (Polymer Preprints 2005, 46(1), 583-584). This monomer was grafted onto cotton fabrics (...

  6. Phosphonate fertilizers suppressed root knot nematodes Meloidogyne javanica and M. incognita

    PubMed Central

    Habash, Samer; Al-Banna, Luma

    2011-01-01

    The efficacy of the phosphonate fertilizers, Calphos® (a.i. calcium phosphonate), Magphos® (a.i. magnesium phosphonate and potassium phosphonate) and Phosphoros® (a.i. potassium phosphonate) against two species of root knot nematodes (RKN), Meloidogyne javanica and M. incognita is evaluated. Laboratory experiments showed that Calphos®, Magphos® and their main components inhibited egg hatching and caused 100% mortality of the second stage juveniles (J2s) of the two RKN species; the hatching inhibition effects persisted after transferring the egg masses of both species to water. However, Phosphoros® (0.5%) did not suppress egg hatching or the survival of J2s of both RKN species. No hatching occurred when egg masses were treated for one week with the nematicide Vydate L® (2 ml/l), however, J2s hatched when the Vydate L® treated egg masses were moved to water. The glasshouse study indicated that Magphos®, Calphos® and Phosphoros® reduced root galling caused by M. javanica by 98, 66 and 47%, respectively, in comparison to the untreated controls. Magphos® resulted in the lowest number of root galls formed by M. incognita, the reduction was 84%. In contrast, Calphos® and Phosphoros® reduced galling by 47 and 39%, respectively. The Magphos® treatment resulted in the lowest numbers of egg masses and the lowest reproductive factor (RF) of both nematode species. However, plants treated with Phosphoros® resulted in higher foliage weights compared with the application of the other two fertilizers and the untreated plants. PMID:22791918

  7. Synthesis and characterization of calcium hydroxy and fluoroapatite functionalized with methyl phosphonic dichloride

    NASA Astrophysics Data System (ADS)

    Agougui, Hassen; Aissa, Abdallah; Debbabi, Mongi

    2012-11-01

    The nature of apatite-organic molecule interaction was the subject of many investigations. Grafting the organic molecule onto the inorganic support may precede through either formation of covalent bonds or ionic interaction between superficial hydroxyl on the apatite surface and organic functions. The hybrid materials obtained by functionalization of apatite surfaces with phosphonate moieties are of interest for their potential applications such in catalysis, chromatography and biomedical domain. In this scope, calcium hydroxyl and fluoroapatite (CaHAp and CaFAp) were prepared in the presence of the methyl phosphonic dichloride (MPO), by contact method in organic solvent at 25 °C for 2 days. The products are rigorously characterized by chemical analysis, infrared (IR), MAS-NMR spectroscopies, powder X-ray diffraction (XRD), atomic force microscopy (AFM) and specific surface area (SSA). The X-ray powder analysis showed that the crystallinity was sensibly affected by the presence of organic moieties. The IR spectroscopy showed new vibration modes appearing related to phosphonate groups essentially at 2930, 1315, 945, 764 and 514 cm-1. The 31P MAS NMR spectrum for hydroxy and fluoroapatite exhibits a single signal at 2.8 ppm. After reaction with (MPO) the spectra show the presence of new signals, assigned to the formation of organic-inorganic bond between the superficial hydroxyl groups of the apatite (tbnd CaOH) and (tbnd POH) and methyl phosphonic dichloride. The SSA decreases with increasing phosphonate amount especially for CaHAp modified by (MPO). AFM indicated that the texture surface was changed by grafting.

  8. The Genes and Enzymes of Phosphonate Metabolism by Bacteria, and Their Distribution in the Marine Environment

    PubMed Central

    Villarreal-Chiu, Juan F.; Quinn, John P.; McGrath, John W.

    2011-01-01

    Phosphonates 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 catalyzed 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. In this report we review the enzymology of C–P bond metabolism in bacteria, and also present the results of an in silico investigation of the distribution of the genes that encode the pathways responsible, in both bacterial genomes and in marine metagenomic libraries, and their likely modes of regulation. Interrogation of currently available whole-genome bacterial sequences indicates that some 10% contain genes encoding putative pathways of phosphonate biosynthesis while ∼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, and it is likely that both substrate-inducible and Pi-repressible mechanisms are involved in their regulation. The data we present 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. PMID:22303297

  9. Modified Nucleoside Triphosphates for In-vitro Selection Techniques

    PubMed Central

    Dellafiore, María A.; Montserrat, Javier M.; Iribarren, Adolfo M.

    2016-01-01

    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. PMID:27200340

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

    PubMed

    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

  11. A Novel and Fast Purification Method for Nucleoside Transporters

    PubMed Central

    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

  12. Synthetic strategies toward carbocyclic purine-pyrimidine hybrid nucleosides.

    PubMed

    Sadler, Joshua M; Mosley, Sylvester L; Dorgan, Kathleen M; Zhou, Zhaohui Sunny; Seley-Radtke, Katherine L

    2009-08-01

    The blending of key structural features from the purine and pyrimidine nucleobase scaffolds gives rise to a new class of hybrid nucleosides. The purine-pyrimidine hybrid nucleosides can be viewed as either N-3 ribosylated purines or 5,6-disubstituted pyrimidines, thus recognition by both purine- and pyrimidine-metabolizing enzymes is possible. Given the increasing reports of the development of resistance in many enzymatic systems, a drug that could be recognized by more than one enzyme could prove highly advantageous in overcoming resistance mechanisms related to binding site mutations. In that regard, the design, synthesis and results of preliminary biological activity for a series of carbocyclic uracil derivatives with either a fused imidazole or thiazole ring are presented herein. PMID:19592260

  13. Synthetic Strategies Toward Carbocyclic Purine-Pyrimidine Hybrid Nucleosides

    PubMed Central

    Sadler, Joshua M.; Mosley, Sylvester L.; Dorgan, Kathleen M.; Zhou, Zhaohui Sunny; Seley-Radtke, Katherine L.

    2009-01-01

    The blending of key structural features from the purine and pyrimidine nucleobase scaffolds gives rise to a new class of hybrid nucleosides. The purine-pyrimidine hybrid nucleosides can be viewed as either N-3 ribosylated purines or 5,6-disubstituted pyrimidines, thus recognition by both purine- and pyrimidine-metabolizing enzymes is possible. Given the increasing reports of the development of resistance in many enzymatic systems, a drug that could be recognized by more than one enzyme could prove highly advantageous in overcoming resistance mechanisms related to binding site mutations. In that regard, the design, synthesis and results of preliminary biological activity for a series of carbocyclic uracil derivatives with either a fused imidazole or thiazole ring are presented herein. PMID:19592260

  14. Modified Nucleoside Triphosphates for In-vitro Selection Techniques.

    PubMed

    Dellafiore, María A; Montserrat, Javier M; Iribarren, Adolfo M

    2016-01-01

    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. PMID:27200340

  15. Compositions containing nucleosides and manganese and their uses

    SciTech Connect

    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.

  16. Overcoming nucleoside analog chemoresistance of pancreatic cancer: A therapeutic challenge

    PubMed Central

    Hung, Sau Wai; Mody, Hardik R.; Govindarajan, Rajgopal

    2013-01-01

    Clinical refractoriness to nucleoside analogs (e.g., gemcitabine, capecitabine) is a major scientific problem and is one of the main reasons underlying the extremely poor prognostic state of pancreatic cancer. The drugs’ effects are suboptimal partly due to cellular mechanisms limiting their transport, activation, and overall efficacy. Nonetheless, novel therapeutic approaches are presently under study to circumvent nucleoside analog resistance in pancreatic cancer. With these new approaches come additional challenges to be addressed. This review describes the determinants of chemoresistance in the gemcitabine cytotoxicity pathways, provides an overview of investigational approaches for overcoming chemoresistance, and discusses new challenges presented. Understanding the future directions of the field may assist in the successful development of novel treatment strategies for enhancing chemotherapeutic efficacy in pancreatic cancer. PMID:22425961

  17. Modified Nucleoside Triphosphates for in-vitro Selection Techniques

    NASA Astrophysics Data System (ADS)

    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.

  18. Localization of GFP-tagged concentrative nucleoside transporters in a renal polarized epithelial cell line.

    PubMed

    Mangravite, L M; Lipschutz, J H; Mostov, K E; Giacomini, K M

    2001-05-01

    Many nucleosides undergo active reabsorption within the kidney, probably via nucleoside transporters. To date, two concentrative nucleoside transporters have been cloned, the sodium-dependent purine-selective nucleoside transporter (SPNT) and concentrative nucleoside transporter 1 (CNT1). We report the stable expression of green fluorescence protein (GFP)-tagged SPNT and CNT1 in Madin-Darby canine kidney (MDCK) cells, a polarized renal epithelial line. We demonstrate that the GFP tag does not alter the substrate selectivity and only modestly affects the kinetic activity of the transporters. By using confocal microscopy and functional studies, both SPNT and CNT1 are localized primarily to the apical membrane of MDCK and LLC-PK(1) cells. Apical localization of these transporters suggests a role in renal nucleoside reabsorption and regulation of tubular function via the adenosine pathway. PMID:11292631

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

    PubMed

    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

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

    PubMed

    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

  1. Evaluation of anti-HIV-1 mutagenic nucleoside analogues.

    PubMed

    Vivet-Boudou, Valérie; Isel, Catherine; El Safadi, Yazan; Smyth, Redmond P; Laumond, Géraldine; Moog, Christiane; Paillart, Jean-Christophe; Marquet, Roland

    2015-01-01

    Because of their high mutation rates, RNA viruses and retroviruses replicate close to the threshold of viability. Their existence as quasi-species has pioneered the concept of "lethal mutagenesis" that prompted us to synthesize pyrimidine nucleoside analogues with antiviral activity in cell culture consistent with an accumulation of deleterious mutations in the HIV-1 genome. However, testing all potentially mutagenic compounds in cell-based assays is tedious and costly. Here, we describe two simple in vitro biophysical/biochemical assays that allow prediction of the mutagenic potential of deoxyribonucleoside analogues. The first assay compares the thermal stabilities of matched and mismatched base pairs in DNA duplexes containing or not the nucleoside analogues as follows. A promising candidate should display a small destabilization of the matched base pair compared with the natural nucleoside and the smallest gap possible between the stabilities of the matched and mismatched base pairs. From this assay, we predicted that two of our compounds, 5-hydroxymethyl-2'-deoxyuridine and 5-hydroxymethyl-2'-deoxycytidine, should be mutagenic. The second in vitro reverse transcription assay assesses DNA synthesis opposite nucleoside analogues inserted into a template strand and subsequent extension of the newly synthesized base pairs. Once again, only 5-hydroxymethyl-2'-deoxyuridine and 5-hydroxymethyl-2'-deoxycytidine are predicted to be efficient mutagens. The predictive potential of our fast and easy first line screens was confirmed by detailed analysis of the mutation spectrum induced by the compounds in cell culture because only compounds 5-hydroxymethyl-2'-deoxyuridine and 5-hydroxymethyl-2'-deoxycytidine were found to increase the mutation frequency by 3.1- and 3.4-fold, respectively. PMID:25398876

  2. Synthesis of oligodeoxyribonucleotides using N-benzyloxycarbonyl-blocked nucleosides

    SciTech Connect

    Watkins, B.E.; Kiely, J.S.; Rapoport, H.

    1982-10-20

    The exo amino groups of 2'-deoxyadenosine and 2'-deoxycytidine have been blocked as the benzyl carbamates, and 2'-deoxyguanosine has been blocked as its 2-N-(benzyloxycarbonyl)carbamate and 6-O-benzyl ether. These blocked nucleosides have been incorporated into an efficient oligodeoxyribonucleotide synthetic scheme, and the resulting oligomer has been successfully deblocked by using transfer hydrogenation. The deblocking conditions result in no reduction of the pyrimidine bases.

  3. Broad-spectrum non-nucleoside inhibitors of human herpesviruses

    PubMed Central

    McClain, Lora; Zhi, Yun; Cheng, Hoyee; Ghosh, Ayantika; Piazza, Paolo; Yee, Michael B.; Kumar, Santosh; Milosevic, Jadranka; Bloom, David C.; Arav-Boger, Ravit; Kinchington, Paul R.; Yolken, Robert; Nimgaonkar, Vishwajit; D’Aiuto, Leonardo

    2015-01-01

    Herpesvirus infections cause considerable morbidity and mortality through lifelong recurrent cycles of lytic and latent infection in several tissues, including the human nervous system. Acyclovir (ACV) and its prodrug, the current antivirals of choice for herpes simplex virus (HSV) and, to some extent, varicella zoster virus (VZV) infections are nucleoside analogues that inhibit viral DNA replication. Rising viral resistance and the need for more effective second-line drugs have motivated searches for additional antiviral agents, particularly non-nucleoside based agents. We evaluated the antiviral activity of five compounds with predicted lysosomotropic activity using conventional and human induced pluripotent stem cell-derived neuronal (iPSC-neurons) cultures. Their potency and toxicity were compared with ACV and the lysosomotropic agents chloroquine and bafilomycin A1. Out of five compounds tested, micromolar concentrations of 30N12, 16F19, and 4F17 showed antiviral activity comparable to ACV (50μM) during lytic herpes simplex virus type 1 (HSV-1) infections, reduced viral DNA copy number, and reduced selected HSV-1 protein levels. These compounds also inhibited the reactivation of ‘quiescent’ HSV-1 infection established in iPSC-neurons, but did not inhibit viral entry into host cells. The same compounds had greater potency than ACV against lytic VZV infection; they also inhibited replication of human cytomegalovirus. The anti-herpetic effects of these non-nucleoside agents merit further evaluation in vivo. PMID:26079681

  4. Nucleobase and nucleoside transport and integration into plant metabolism

    PubMed Central

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

    2014-01-01

    Nucleotide metabolism is an essential process in all living organisms. Besides newly synthesized nucleotides, the recycling (salvage) of partially degraded nucleotides, i.e., nucleosides and nucleobases serves to keep the homeostasis of the nucleotide pool. Both types of metabolites are substrates of at least six families of transport proteins in Arabidopsis thaliana (Arabidopsis) with a total of 49 members. In the last years several members of such transport proteins have been analyzed allowing to present a more detailed picture of nucleoside and nucleobase transport and the physiological function of these processes. Besides functioning in nucleotide metabolism it turned out that individual members of the before named transporters exhibit the capacity to transport a wide range of different substrates including vitamins and phytohormones. The aim of this review is to summarize the current knowledge on nucleobase and nucleoside transport processes in plants and integrate this into nucleotide metabolism in general. Thereby, we will focus on those proteins which have been characterized at the biochemical level. PMID:25250038

  5. Broad-spectrum non-nucleoside inhibitors of human herpesviruses.

    PubMed

    McClain, Lora; Zhi, Yun; Cheng, Hoyee; Ghosh, Ayantika; Piazza, Paolo; Yee, Michael B; Kumar, Santosh; Milosevic, Jadranka; Bloom, David C; Arav-Boger, Ravit; Kinchington, Paul R; Yolken, Robert; Nimgaonkar, Vishwajit; D'Aiuto, Leonardo

    2015-09-01

    Herpesvirus infections cause considerable morbidity and mortality through lifelong recurrent cycles of lytic and latent infection in several tissues, including the human nervous system. Acyclovir (ACV) and its prodrug, the current antivirals of choice for herpes simplex virus (HSV) and, to some extent, varicella zoster virus (VZV) infections are nucleoside analogues that inhibit viral DNA replication. Rising viral resistance and the need for more effective second-line drugs have motivated searches for additional antiviral agents, particularly non-nucleoside based agents. We evaluated the antiviral activity of five compounds with predicted lysosomotropic activity using conventional and human induced pluripotent stem cell-derived neuronal (iPSC-neurons) cultures. Their potency and toxicity were compared with ACV and the lysosomotropic agents chloroquine and bafilomycin A1. Out of five compounds tested, micromolar concentrations of 30N12, 16F19, and 4F17 showed antiviral activity comparable to ACV (50μM) during lytic herpes simplex virus type 1 (HSV-1) infections, reduced viral DNA copy number, and reduced selected HSV-1 protein levels. These compounds also inhibited the reactivation of 'quiescent' HSV-1 infection established in iPSC-neurons, but did not inhibit viral entry into host cells. The same compounds had greater potency than ACV against lytic VZV infection; they also inhibited replication of human cytomegalovirus. The anti-herpetic effects of these non-nucleoside agents merit further evaluation in vivo. PMID:26079681

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

    PubMed

    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

  7. Aqueous microwaves assisted cross-coupling reactions applied to unprotected nucleosides.

    NASA Astrophysics Data System (ADS)

    Len, Christophe; Hervé, Gwénaelle

    2015-02-01

    Nucleoside analogues have attracted much attention due to their potential biological activities. Amongst all synthetic nucleosides, C5-modified pyrimidines and C7- or C8-modified purines have mostly been prepared using palladium cross-coupling reactions and then studied as antitumoral and antiviral agents. Our objective is to focus this review on the Suzuki-Miyaura and on the Heck cross-couplings of nucleosides using microwave irradiations which are an alternative technology compatible with green chemistry and sustainable development.

  8. Dual Catalysis Using Boronic Acid and Chiral Amine: Acyclic Quaternary Carbons via Enantioselective Alkylation of Branched Aldehydes with Allylic Alcohols.

    PubMed

    Mo, Xiaobin; Hall, Dennis G

    2016-08-31

    A ferrocenium boronic acid salt activates allylic alcohols to generate transient carbocations that react with in situ-generated chiral enamines from branched aldehydes. The optimized conditions afford the desired acyclic products embedding a methyl-aryl quaternary carbon center with up to 90% yield and 97:3 enantiomeric ratio, with only water as the byproduct. This noble-metal-free method complements alternative methods that are incompatible with carbon-halogen bonds and other sensitive functional groups. PMID:27518200

  9. Investigating temporary acyclicity in a captive group of Asian elephants (Elephas maximus): Relationship between management, adrenal activity and social factors.

    PubMed

    Edwards, Katie L; Trotter, Jessica; Jones, Martin; Brown, Janine L; Steinmetz, Hanspeter W; Walker, Susan L

    2016-01-01

    Routine faecal steroid monitoring has been used to aid the management of five captive Asian elephant (Elephas maximus) females at Chester Zoo, UK, since 2007. Progestagen analysis initially revealed synchronised oestrous cycles among all females. However, a 14- to 20-week period of temporary acyclicity subsequently occurred in three females, following several management changes (increased training, foot-care and intermittent matriarch removal for health reasons) and the initiation of pregnancy in another female. The aim of this study was to retrospectively investigate whether these management changes were related to increased adrenal activity and disruption of ovarian activity, or whether social factors may have been involved in the temporary cessation of cyclicity. Faecal samples collected every other day were analysed to investigate whether glucocorticoid metabolites were related to reproductive status (pregnant, cycling, acyclic) or management (training, foot-care, matriarch presence). Routine training and foot-care were not associated with adrenal activity; however, intensive foot-care to treat an abscess in one female was associated with increased glucocorticoid concentration. Matriarch presence influenced adrenal activity in three females, being lower when the matriarch was separated from the group at night compared to being always present. However, in the females that exhibited temporary acyclicity, there was no consistent relationship between glucocorticoids and cyclicity state. Although the results of this study do not fully explain this occurrence, the highly synchronised nature of oestrous cycles within this group, and the concurrent acyclicity in three females, raises the question of whether social factors could have been involved in the temporary disruption of ovarian activity. PMID:26393308

  10. Iterative Coupling of Two Different Enones by Nitromethane Using Bifunctional Thiourea Organocatalysts. Stereocontrolled Assembly of Cyclic and Acyclic Structures.

    PubMed

    Varga, Szilárd; Jakab, Gergely; Csámpai, Antal; Soós, Tibor

    2015-09-18

    An organocatalytic iterative assembly line has been developed in which nitromethane was sequentially coupled with two different enones using a combination of pseudoenantiomeric cinchona-based thiourea catalysts. Application of unsaturated aldehydes and ketones in the second step of the iterative sequence allows the construction of cyclic syn-ketols and acyclic compounds with multiple contiguous stereocenters. The combination of the multifunctional substrates and ambident electrophiles rendered some organocatalytic transformations possible that have not yet been realized in bifunctional noncovalent organocatalysis. PMID:26301563

  11. Use of new phosphonylating and coupling agents in the synthesis of oligodeoxyribonucleotides via the H-phosphonate approach.

    PubMed Central

    Sakatsume, O; Yamane, H; Takaku, H; Yamamoto, N

    1990-01-01

    New phosphonylating and coupling agents for the synthesis of oligodeoxyribonucleotides via H-phosphonate approach have been developed. Tris(1,1,1,3,3,3-hexafluoro-2-propyl) phosphite, prepared by the reaction of lithium salt of 1,1,1,3,3,3-hexafluoro-2-propoxide with PCl3, reacts with deoxyribonucleosides in the presence of a catalytic amount of triethylamine to produce in the high yield the corresponding deoxyribonucleoside 3'-H-phosphonate units. The use of a new coupling reagent, 1,3-dimethyl-2-chloro-imidazolinium chloride (DMCI) for the internucleotidic H-phosphonate bond formation via the H-phosphonate approach is also discussed in detail. Images PMID:2356122

  12. A review of non-nucleoside anti-hepatitis B virus agents.

    PubMed

    Zhang, Fan; Wang, Gang

    2014-03-21

    Hepatitis B Virus is the most common cause of chronic liver disease worldwide. Currently approved agents of chronic HBV infection treatment include interferon and nucleoside analogues. However, the side effects of interferon and the viral resistance of nucleoside analogues make the current treatment far from satisfactory. Therefore, new drugs with novel structures and mechanisms are needed. Recently, a number of non-nucleoside HBV inhibitors have been obtained from natural sources or prepared by synthesis/semi-synthesis. Some of them exhibited potent anti-HBV activity with novel mechanisms. These compounds provide useful information for the medicinal chemist to develop novel non-nucleoside compounds as anti-HBV agents. PMID:24549242

  13. Nucleoside transport at the blood-testis barrier studied with primary-cultured sertoli cells.

    PubMed

    Kato, Ryo; Maeda, Tomoji; Akaike, Toshihiro; Tamai, Ikumi

    2005-02-01

    Nucleosides are essential for nucleotide synthesis in testicular spermatogenesis. In the present study, the mechanism of the supply of nucleosides to the testicular system across the blood-testis barrier was studied using primary-cultured Sertoli cells from rats and TM4 cells from mice. Uptake of uridine by these cells was time- and concentration-dependent. Uridine uptake was decreased under Na(+)-free conditions, and the system was presumed to be high affinity, indicating an Na(+)-dependent concentrative nucleoside transporter (CNT) is involved. On the other hand, nitrobenzylthioinosine, a potent inhibitor of Na(+)-independent equilibrative nucleoside transporters (ENTs), inhibited uridine uptake by the Sertoli cells in a concentration-dependent manner. Expression of nucleoside transporters ENT1, ENT2, ENT3, CNT1, CNT2, and CNT3 was detected in Sertoli cells by reverse transcriptase-polymerase chain reaction analysis. Inhibition studies of the uptake of uridine by various nucleosides both in the presence and absence of Na(+) indicated that the most of those expressed nucleoside transporters, ENTs and CNTs, are involved functionally. These results demonstrated that Sertoli cells are equipped with multiple nucleoside transport systems, including ENT1, ENT2, and CNTs, to provide nucleosides for spermatogenesis. PMID:15547112

  14. Nucleosides of 4-methylthio-1,2,3-triazol-5-yl-carboxylic acid derivatives

    SciTech Connect

    Shingarova, I.D.; Yartseva, I.V.; Preobrazhenskaya, M.N.

    1987-08-01

    2-..beta..-D-Ribofuranosyl-4-methylthio-5-methoxycarbonyl-1,2,3-triazole was obtained by fusing 4-methylthio-5-methoxycarbonyl-1,2,3-triazole together with tetraacyl-D-ribofuranose, followed by deacylation, and its amide and hydrazide were prepared. The structures of the new nucleosides were established by converting them into known 2-nucleosides of 1,2,3-triazol-4-yl-carboxylic acid derivatives. By comparing PMR spectra with previously reported PMR spectra for the isomeric 1- and 2-nucleosides of 1,2,3-triazol-4-yl-carboxylic acid derivatives, the synthesized nucleosides could be assigned to 2-substituted triazoles.

  15. Chemical Logic and Enzymatic Machinery for Biological Assembly of Peptidyl Nucleoside Antibiotics

    PubMed Central

    Walsh, Christopher T.; Zhang, Wenjun

    2011-01-01

    Peptidyl nucleoside antibiotics are a group of natural products targeting MraY, a bacterial translocase involved in the lipid-linked cycle in peptidoglycan biosynthesis. In this Perspective, we explore how Nature builds complex peptidyl nucleoside antibiotics scaffolds from simple nucleoside and amino acid building blocks. We discuss the current stage of research on biosynthetic pathways for peptidyl nucleoside antibiotics, primarily focusing on chemical logic and enzymatic machinery for uridine transformation and coupling to peptides. We further survey the nonribosomal biosynthetic paradigm for a subgroup of uridyl peptide antibiotics represented by pacidamycins, concluded by diversification opportunities for antibiotic optimization. PMID:21851099

  16. A metal-containing nucleoside that possesses both therapeutic and diagnostic activity against cancer.

    PubMed

    Choi, Jung-Suk; Maity, Ayan; Gray, Thomas; Berdis, Anthony J

    2015-04-10

    Nucleoside transport is an essential process that helps maintain the hyperproliferative state of most cancer cells. As such, it represents an important target for developing diagnostic and therapeutic agents that can effectively detect and treat cancer, respectively. This report describes the development of a metal-containing nucleoside designated Ir(III)-PPY nucleoside that displays both therapeutic and diagnostic properties against the human epidermal carcinoma cell line KB3-1. The cytotoxic effects of Ir(III)-PPY nucleoside are both time- and dose-dependent. Flow cytometry analyses validate that the nucleoside analog causes apoptosis by blocking cell cycle progression at G2/M. Fluorescent microscopy studies show rapid accumulation in the cytoplasm within 4 h. However, more significant accumulation is observed in the nucleus and mitochondria after 24 h. This localization is consistent with the ability of the metal-containing nucleoside to influence cell cycle progression at G2/M. Mitochondrial depletion is also observed after longer incubations (Δt ∼48 h), and this effect may produce additional cytotoxic effects. siRNA knockdown experiments demonstrate that the nucleoside transporter, hENT1, plays a key role in the cellular entry of Ir(III)-PPY nucleoside. Collectively, these data provide evidence for the development of a metal-containing nucleoside that functions as a combined therapeutic and diagnostic agent against cancer. PMID:25713072

  17. Purine nucleoside modulation of functions of human lymphocytes.

    PubMed

    Priebe, T; Platsoucas, C D; Seki, H; Fox, F E; Nelson, J A

    1990-09-01

    The accumulation of endogenous substrates in patients with adenosine deaminase deficiency or purine nucleoside phosphorylase deficiency is believed to be responsible for the immunodeficiency observed in these patients. To identify the lymphocyte populations that are most susceptible to these substrates, we investigated the effect of their nucleoside analogs on a number of T and B cell functions of human lymphocytes. We found that tubercidin (Tub), 2-chloro 2'deoxyadenosine (2CldA), 2-fluoro adenine arabinoside-5'phosphate (FaraAMP), and 9-beta-D-arabinosyl guanine (AraGua) inhibited the proliferative responses of human peripheral blood mononuclear cells (PBMC) to polyclonal activators (PHA, OKT3 mab) or to allogeneic PBMC in mixed lymphocyte cultures (MLC). Addition of recombinant IL-2 from the beginning of the culture did not alter the inhibition by Tub of the proliferative responses of PBMC. These purine nucleoside analogs also inhibited the proliferative responses of purified human peripheral blood CD4+ and CD8+ T cells to PHA and of purified B cells to SAC. The concentrations of these nucleosides required to achieve a given degree of inhibition of proliferative responses of T lymphocyte subpopulations or B cells was similar, suggesting that these analogs do not exhibit any selectivity for these purified lymphocyte populations. Tub and FaraAMP, respectively, inhibited and enhanced, at the effector phase, both NK cytotoxicity and specific T cell-mediated cytotoxicity. In contrast to these findings, LAK cytotoxicity at the effector phase was not significantly inhibited by Tub, and was not enhanced by FaraAMP. Both analogs inhibited rIL-2-induced proliferative responses of PBMC, but did not affect the generation of LAK cytotoxicity (induction phase) against the K562 targets when added at the beginning of the culture. This suggests that DNA synthesis is not required for LAK cell induction. Both Tub and FaraAMP inhibited immunoglobulin production (IgG and IgM) by

  18. Purine nucleoside phosphorylase as a cytosolic arsenate reductase.

    PubMed

    Gregus, Zoltán; Németi, Balázs

    2002-11-01

    The findings of the accompanying paper (Németi and Gregus, Toxicol: Sci. 70, 4-12) indicate that the arsenate (AsV) reductase activity of rat liver cytosol is due to an SH enzyme that uses phosphate (or its analogue, arsenate, AsV) and a purine nucleoside (guanosine or inosine) as substrates. Purine nucleoside phosphorylase (PNP) is such an enzyme. It catalyzes the phosphorolytic cleavage of 6-oxopurine nucleosides according to the following scheme: guanosine (or inosine) + phosphate <--> guanine (or hypoxanthine) + ribose-1-phosphate. Therefore, we have tested the hypothesis that PNP is responsible for the thiol- and purine nucleoside-dependent reduction of AsV to AsIII by rat liver cytosol. AsIII formed from AsV was quantified by HPLC-hydride generation-atomic fluorescence spectrometry analysis of the deproteinized incubates. The following findings support the conclusion that PNP reduces AsV to AsIII, using AsV instead of phosphate in the reaction above: (1) Specific PNP inhibitors (CI-1000, BCX-1777) at a concentration of 1 microM completely inhibited cytosolic AsV reductase activity. (2) During anion-exchange chromatography of cytosolic proteins, PNP activity perfectly coeluted with the AsV reductase activity, suggesting that both activities belong to the same protein. (3) PNP purified from calf spleen catalyzed reduction of AsV to AsIII in the presence of dithiothreitol (DTT) and a 6-oxopurine nucleoside (guanosine or inosine). (4) AsV reductase activity of purified PNP, like the cytosolic AsV reductase activity, was inhibited by phosphate (a substrate of PNP alternative to AsV), guanine and hypoxanthine (products of PNP favoring the reverse reaction), mercurial thiol reagents (nonspecific inhibitors of PNP), as well as CI-1000 and BCX-1777 (specific PNP inhibitors). Thus, PNP appears to be responsible for the AsV reductase activity of rat liver cytosol in the presence of DTT. Further research should clarify the mechanism and the in vivo significance of PNP

  19. Spatially Modulating Interfacial Properties of Transparent Conductive Oxides: Patterning Work Function with Phosphonic Acid Self-Assembled Monolayers

    SciTech Connect

    Knesting, Kristina M.; Hotchkiss, Peter J.; MacLeod, Bradley A.; Marder, Seth R.; Ginger, David S.

    2011-09-29

    The interface between an organic semiconductor and a transparent conducting oxide is crucial to the performance of organic optoelectronics. We use microcontact printing to pattern pentafluorobenzyl phosphonic acid self-assembled monolayers (SAMs) on indium tin oxide (ITO). We obtain high-fidelity patterns with sharply defined edges and with large work function contrast (comparable to that obtained from phosphonic acid SAMs deposited from solution).

  20. Conserved Glutamate Residues Glu-343 and Glu-519 Provide Mechanistic Insights into Cation/Nucleoside Cotransport by Human Concentrative Nucleoside Transporter hCNT3*

    PubMed Central

    Slugoski, Melissa D.; Smith, Kyla M.; Ng, Amy M. L.; Yao, Sylvia Y. M.; Karpinski, Edward; Cass, Carol E.; Baldwin, Stephen A.; Young, James D.

    2009-01-01

    Human concentrative nucleoside transporter 3 (hCNT3) utilizes electrochemical gradients of both Na+ and H+ to accumulate pyrimidine and purine nucleosides within cells. We have employed radioisotope flux and electrophysiological techniques in combination with site-directed mutagenesis and heterologous expression in Xenopus oocytes to identify two conserved pore-lining glutamate residues (Glu-343 and Glu-519) with essential roles in hCNT3 Na+/nucleoside and H+/nucleoside cotransport. Mutation of Glu-343 and Glu-519 to aspartate, glutamine, and cysteine severely compromised hCNT3 transport function, and changes included altered nucleoside and cation activation kinetics (all mutants), loss or impairment of H+ dependence (all mutants), shift in Na+:nucleoside stoichiometry from 2:1 to 1:1 (E519C), complete loss of catalytic activity (E519Q) and, similar to the corresponding mutant in Na+-specific hCNT1, uncoupled Na+ currents (E343Q). Consistent with close-proximity integration of cation/solute-binding sites within a common cation/permeant translocation pore, mutation of Glu-343 and Glu-519 also altered hCNT3 nucleoside transport selectivity. Both residues were accessible to the external medium and inhibited by p-chloromercuribenzene sulfonate when converted to cysteine. PMID:19380587

  1. Computer simulations of cyclic and acyclic cholinergic agonists: conformational search and molecular dynamics simulations.

    PubMed Central

    McGroddy, K A; Brady, J W; Oswald, R E

    1994-01-01

    Molecular dynamics simulations have been performed on aqueous solutions of two chemically similar nicotinic cholinergic agonists in order to compare their structural and dynamical differences. The cyclic 1,1-dimethyl-4-acetylpiperazinium iodide (HPIP) molecule was previously shown to be a strong agonist for nicotinic acetylcholine receptors (McGroddy et al., 1993), while the acyclic N,N,N,N'-tetramethyl-N'-acetylethylenediamine iodide (HTED) derivative is much less potent. These differences were expected to arise from differences in the solution structures and internal dynamics of the two molecules. HPIP was originally thought to be relatively rigid; however, molecular dynamics simulations suggest that the acetyl portion of the molecule undergoes significant ring dynamics on a psec timescale. The less constrained HTED molecule is relatively rigid, with only one transition observed about any of the major dihedrals in four 100 psec simulations, each started from a different conformation. The average structures obtained from the simulations are very similar to the starting minimized structure in each case, except for the HTED simulation where a single rotation about the N-C-C-N(+) backbone occurred. In each case, HTED had three to five more water molecules in its primary solvation shell than HPIP, indicating that differences in the energetics of desolvation before binding may partially explain the increased potency of HPIP as compared to HTED. Images FIGURE 1 FIGURE 2 PMID:8161685

  2. Amino acids of the Murchison meteorite. I - Six carbon acyclic primary alpha-amino alkanoic acids

    NASA Technical Reports Server (NTRS)

    Cronin, J. R.; Gandy, W. E.; Pizzarello, S.

    1981-01-01

    Six of the seven chain isomers of six-carbon acyclic primary alpha-amino alkanoic acids (leucine isomers) have been either identified or confirmed in hot-water extracts of the Murchison meteorite using combined gas chromatography-mass spectrometry (GC-MS) and ion exchange chromatography. 2-Amino-2-ethylbutyric acid, 2-amino-2,3-dimethylbutyric acid, pseudoleucine, and 2-methylnorvaline were positively identified by GC-MS. These amino acids have not been previously reported to occur in natural materials and may be uniquely meteoritic in origin. The presence of leucine and isoleucine (including the diastereoisomer, alloisoleucine) was confirmed. Peaks corresponding to norleucine were seen by ion-exchange and gas chromatography but characteristic mass spectra were not obtained. The alpha-branched chain isomers in this series are quantitatively the most significant. These results are compared with literature data on amino acid synthesis by electrical discharge and Fischer-Tropsch-type catalysis. Neither model system produces an amino acid suite that is completely comparable to that found in the Murchison meteorite.

  3. Amino acids of the Murchison meteorite. III - Seven carbon acyclic primary alpha-amino alkanoic acids

    NASA Technical Reports Server (NTRS)

    Cronin, John R.; Pizzarello, Sandra

    1986-01-01

    All of the eighteen possible seven-carbon acyclic primary alpha-amino alkanoic acids have been positively identified in a hot-water extract of the Murchison meteorite by the combined use of gas chromatography-mass spectrometry, ion exchange chromatography and reversed-phase chromatography. None of these amino acids has previously been found in meteorites or in any other natural material. They range in concentration from less than or equal to 0.5 to 5.3 nmol/g. Configuration assignments were made for 2-amino-3,4-dimethylpentanoic acid and allo-2-amino-3,4-dimethylpentanoic acid and the diasteromer ratio was determined. Fifty-five amino acids have now been positively identified in the Murchison meteorite, 36 of which are unknown in terrestrial materials. This unique suite of amino acids is characterized by the occurrence of all structural isomers within the two major classes of amino acids represented, by the predominance of branched chain isomers, and by an exponential decline in amount with increasing carbon chain length within homologous series. These characteristics of the Murchison amino acids are suggestive of synthesis before incorporation into a parent body.

  4. Source diagnostic and weathering indicators of tar balls utilizing acyclic, polycyclic and S-heterocyclic components.

    PubMed

    Hegazi, A H; Andersson, J T; Abu-Elgheit, M A; El-Gayar, M Sh

    2004-05-01

    This study represents a forensic chemical analysis to define the liability for the coastal bitumens polluting the beaches of the Mediterranean city of Alexandria. Six tar balls collected from several locations along the coast of the city were analyzed for their acyclic and polycyclic hydrocarbons as well as sulfur heterocycles using GC/FID, GC/AED and gas chromatography/mass spectrometry techniques. The analysis of one Egyptian crude oil is also included as a possible source oil. The tar ball samples were at early stages of weathering. Based on the GC traces and biomarker signatures, the tar balls could be genetically different. One sample collected from the Eastern Harbor region appears to be a Bunker C type fuel produced from Egyptian crudes. The refining process has removed the low molecular weight components. On the other hand, the wide n-alkane distribution together with the absence of an unresolved complex mixture suggests that crude oils probably from tank washings, ballast discharges or accident spills from tankers could have contributed significantly to the other tar ball samples. The distribution of source specific hopane and sterane markers revealed that the tar samples probably originate from different oil fields. PMID:15051374

  5. In vitro susceptibility of fungi to acyclic inhibitors of 2,3-oxidosqualene cyclases.

    PubMed

    Airaudi, D; Ceruti, M; Bianco, C; Filipello Marchisio, V

    1996-01-01

    In the present study we determine the antifungal properties of two acyclic inhibitors of 2,3-oxidosqualene cyclases: 22,23-epoxy-2-aza-2,3-dihydrosqualene (EAS) and azasqualene alcohol (ASA). Fungistatic and fungicidal activity towards dermatophytes and other fungi involved in cutaneous and systemic infections was tested (48 isolates from 10 species). The tests were carried out by inoculating 10 microliters of mycelial homogenate in 1 ml of Sabouraud glucose liquid medium containing serial dilutions of 100 to 0.25 micrograms ml-1 of the substance. For each isolate, the minimum inhibitory concentration (MIC) and the minimum fungicidal concentration (MFC) of both compounds were determined. EAS was more active (MIC range 1.5-25 micrograms ml-1) than ASA (MIC range 3-50 micrograms ml-1). At the highest concentration tested, EAS also showed fungicidal action towards some isolates of Trichophyton mentagrophytes, T. terrestre, Epidermophyton floccosum, Microsporum canis and Scopulariopsis brumptii. The most sensitive species was T. mentagrophytes, the most resistant T. rubrum. PMID:8786759

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

    NASA Technical Reports Server (NTRS)

    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.

  7. Flotation properties of some oxygen-containing compounds of the acyclic series

    SciTech Connect

    Shreider, E.M.; Para, S.F.; Galanov, M.E.; Trachik, T.L.; Lagutina, L.V.

    1981-01-01

    In the monatomic alcohols series, maximum flotation activity is reached at 6 to 8 carbon atoms in the radical. It was decided to investigate the reagent properties of some other substances containing hydroxyl radicals which have not previously been considered. Oxygen-containing compounds in the acyclic series were examined, including alcohols: I - ethanol, ethylene-glycol, glycerol, pentaerythrytol, D-mannitol; II - dulcitol, D-sorbitol, D-mannitol, xylitol; glycols - monoethyleneglycol, diethyleneglycol, triethyleneglycol, polyethyleneglycol; and ethanolamines - ethanolamine, triethanolamine. The flotation properties of the reagents were determined in a Mekhanobr laboratory flotation machine with a chamber volume of 1.5 liter and an impeller speed of 1800 rpm. The materials tested were the <1 mm size fractions from run-of-plant charge and slurry from the radial thickeners. The samples were first dried and averaged. The pulp density was 200 g/l. The reagent conditions were kept constant throughout (50% of the total added at the start of a test, 25% after 2 min and 25% after 4 min from the start). The reagent additions were 1.0 to 1.4 kg/ton. All of these compounds had a very weak flotation activity.

  8. Polarizable Empirical Force Field for Acyclic Poly-Alcohols Based on the Classical Drude Oscillator

    PubMed Central

    He, Xibing; Lopes, Pedro E. M.; MacKerell, Alexander D.

    2014-01-01

    A polarizable empirical force field for acyclic polyalcohols based on the classical Drude oscillator is presented. The model is optimized with an emphasis on the transferability of the developed parameters among molecules of different sizes in this series and on the condensed-phase properties validated against experimental data. The importance of the explicit treatment of electronic polarizability in empirical force fields is demonstrated in the cases of this series of molecules with vicinal hydroxyl groups that can form cooperative intra- and intermolecular hydrogen bonds. Compared to the CHARMM additive force field, improved treatment of the electrostatic interactions avoids overestimation of the gas-phase dipole moments, results in significant improvement in the treatment of the conformational energies, and leads to the correct balance of intra- and intermolecular hydrogen bonding of glycerol as evidenced by calculated heat of vaporization being in excellent agreement with experiment. Computed condensed phase data, including crystal lattice parameters and volumes and densities of aqueous solutions are in better agreement with experimental data as compared to the corresponding additive model. Such improvements are anticipated to significantly improve the treatment of polymers in general, including biological macromolecules. PMID:23703219

  9. beta-Lactamase-catalyzed hydrolysis of acyclic depsipeptides and acyl transfer to specific amino acid acceptors.

    PubMed Central

    Pratt, R F; Govardhan, C P

    1984-01-01

    beta-Lactamases from all three classes, A, B, and C, catalyze the hydrolysis of specific acyclic depsipeptide (PhCH2CONHCR1R2CO2CHR3CO2H) analogs of acyl-D-alanyl-D-alanine peptides. The depsipeptides investigated, which are chemically as reactive toward nucleophiles as penicillins, are in general poor substrates, although differences between the classes of beta-lactamases have been observed: the order of effectiveness seems to be C greater than B greater than A. Certain class A and C beta-lactamases also catalyze phenylacetylglycyl transfer between phenylacetylglycyl depsipeptides and specific amino acid acceptors, a type of reaction hitherto identified more closely with D-alanyl-D-alanine transpeptidases than with beta-lactamases. Preliminary indications of an acyl-enzyme intermediate in these reactions have been obtained. These results support the suggestion [Tipper, D.J. and Strominger, J.L. (1965) Proc. Natl. Acad. Sci. USA 54, 1133-1141] that beta-lactamases are evolutionary descendants of bacterial cell wall D-alanyl-D-alanine transpeptidases. PMID:6424114

  10. Analytic Bounds on Causal Risk Differences in Directed Acyclic Graphs Involving Three Observed Binary Variables

    PubMed Central

    Kaufman, Sol; Kaufman, Jay S.; MacLehose, Richard F.

    2009-01-01

    We apply a linear programming approach which uses the causal risk difference (RDC) as the objective function and provides minimum and maximum values that RDC can achieve under any set of linear constraints on the potential response type distribution. We consider two scenarios involving binary exposure X, covariate Z and outcome Y. In the first, Z is not affected by X, and is a potential confounder of the causal effect of X on Y. In the second, Z is affected by X and intermediate in the causal pathway between X and Y. For each scenario we consider various linear constraints corresponding to the presence or absence of arcs in the associated directed acyclic graph (DAG), monotonicity assumptions, and presence or absence of additive-scale interactions. We also estimate Z-stratum-specific bounds when Z is a potential effect measure modifier and bounds for both controlled and natural direct effects when Z is affected by X. In the absence of any additional constraints deriving from background knowledge, the well-known bounds on RDc are duplicated: −Pr(Y≠X) ≤ RDC ≤ Pr(Y=X). These bounds have unit width, but can be narrowed by background knowledge-based assumptions. We provide and compare bounds and bound widths for various combinations of assumptions in the two scenarios and apply these bounds to real data from two studies. PMID:20161106

  11. 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.

    PubMed

    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. PMID:25863571

  12. Polysulfone functionalized with phosphonated poly(pentafluorostyrene) grafts for potential fuel cell applications.

    PubMed

    Dimitrov, Ivaylo; Takamuku, Shogo; Jankova, Katja; Jannasch, Patric; Hvilsted, Søren

    2012-08-28

    A multi-step synthetic strategy to polysulfone (PSU) grafted with phosphonated poly(pentafluorostyrene) (PFS) is developed. It involves controlled radical polymerization resulting in alkyne-end functional PFS. The next step is the modification of PSU with a number of azide side groups. The grafting 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. PMID:22623205

  13. Synthesis, antimicrobial, and alkylating properties of 3-phosphonic derivatives of chromone.

    PubMed

    Budzisz, E; Nawrot, E; Malecka, M

    2001-12-01

    Dimethyl 2,6-dimethyl-4-oxo-4H-chromen-3-yl-phosphonate (1a) and dimethyl 6-methyl-2-phenyl-4-oxo-4H-chromen-3-yl-phosphonate (1b) were synthesized and reacted with primary aliphatic amines to yield title compounds 4-6. Their antibacterial properties against Gram-positive and Gram-negative bacteria strains were tested by the MIC method. Four of seventeen tested compounds (1d, 3, 4a, and 4b) exhibit detectable activity against S. aureus. Some representative examples of newly synthesized compounds were tested for their alkylating properties in vitro in the Preussmann test. Compounds 1a, 1c, 1d, 3, 5d, and 6a possess highly alkylating activity toward standard derivative 4-(4'-nitrobenzyl)pyridine (NBP). PMID:11852533

  14. Synthetic molecular receptors for phosphates and phosphonates in sol-gel materials

    SciTech Connect

    Sasaki, D.Y.; Alam, T.M.; Assink, R.A.

    1997-12-01

    Synthetic receptors for phosphates and phosphonates have been generated in SiO{sub 2} xerogels via a surface molecular imprinting method. The monomer 3-trimethoxy silylpropyl-1-guanidinium chloride (1) was developed to prepare receptor sites capable of binding with substrates through a combination of ionic and hydrogen bond interactions. HPLC studies and adsorption isotherms performed in water have found that molecular imprinting affords a significant improvement in K{sub a} for phosphate and phosphonate affinity over a randomly functionalized xerogel. Affinities for these materials offer about an order of magnitude improvement in affinity compared to analogous small molecule receptors reported in the literature. The xerogel matrix appears to participate in host-guest interactions through anionic charge buildup with increasing pH.

  15. Synthesis and characterization of ruthenium and rhenium dyes with phosphonate anchoring groups.

    PubMed

    Braumüller, Markus; Schulz, Martin; Staniszewska, Magdalena; Sorsche, Dieter; Wunderlin, Markus; Popp, Jürgen; Guthmuller, Julien; Dietzek, Benjamin; Rau, Sven

    2016-05-31

    , a series of rhenium(i) tricarbonyl chloride complexes with bpy-R2 derivatives (bpy = 2,2'-bipyridine, R represents the substitution at the 4- and 4'-positions), and their corresponding trishomoleptic as well as heteroleptic ruthenium(ii) complexes and have been synthesized and characterized. Their applicability as immobilizable metal-organic chromophores in solar and photosynthesis cells is enabled by R, since it includes phosphonic ester groups as precursors for potent phosphonate anchoring groups. Conjugated linkers (phenylene and triazole moieties) serve as distance control between bpy and the anchor. Photophysical and electrochemical studies reveal pronounced effects of the aryl substitution. These effects were further investigated using resonance Raman experiments and supported by theoretical calculations. After hydrolysis the triazole containing was successfully immobilized on NiO, suggesting that its application in photovoltaic cells is feasible. The solid state structures of , , and are reported in this paper, enabling the determination of the distances and intermolecular interactions. PMID:27172842

  16. Preparation of sup 35 S-labeled polyphosphorothioate oligodeoxyribonucleotides by use of hydrogen phosphonate chemistry

    SciTech Connect

    Stein, A.; Iversen, P.L.; Subasinghe, C.; Cohen, J.S.; Stec, W.J.; Zon, G. )

    1990-07-01

    The title compounds were chemically synthesized as their 5'-dimethoxytrityl derivatives by base-catalyzed reaction of {sup 35}S-enriched elemental sulfur with support-bound hydrogen phosphonate oligomer. This was derived from adamantane carbonyl chloride-activated coupling of nucleotide hydrogen phosphonate monomers, and similarly activated capping with isopropyl phosphite. A convenient, disposable, reversed-phase cartridge was utilized to purify and isolate the 5'-dimethoxytrityl derivative for subsequent in situ detritylation and elution of the final product. The specific activity obtained for the title compounds was ca. 10(7) cpm/mumols-eq P(O)S-. The procedure should be readily adaptable to appropriate syntheses of other P-S containing analogs of DNA and RNA.

  17. Peptide length and prime-side sterics influence potency of peptide phosphonate protease inhibitors

    PubMed Central

    Brown, Christopher M.; Ray, Manisha; Eroy-Reveles, Aura A.; Egea, Pascal; Tajon, Cheryl; Craik, Charles S.

    2010-01-01

    Summary The ability to follow enzyme activity in a cellular context represents a challenging technological frontier that impacts fields ranging from disease pathogenesis to epigenetics. Activity-based probes (ABPs) label the active form of an enzyme via covalent modification of catalytic residues. Here we present an analysis of parameters influencing potency of peptide phosphonate ABPs for trypsin-fold S1A proteases, an abundant and important class of enzymes with similar substrate specificities. We find that peptide length and stability influence potency more than sequence composition and present structural evidence that steric interactions at the prime-side of the substrate-binding cleft affect potency in a protease-dependent manner. We introduce guidelines for the design of peptide phosphonate ABPs and demonstrate their utility in a live-cell labeling application that specifically targets active S1A proteases at the cell surface of cancer cells. PMID:21276938

  18. An unprecedented zero field neodymium(iii) single-ion magnet based on a phosphonic diamide.

    PubMed

    Gupta, Sandeep K; Rajeshkumar, Thayalan; Rajaraman, Gopalan; Murugavel, Ramaswamy

    2016-06-01

    The axial ligation by the -P[double bond, length as m-dash]O group of a phosphonic diamide in an air-stable Nd(iii) complex ensures a pseudo-D5h symmetry leading to the stabilization of the mJ = |±9/2〉 state; this in turn is responsible for the observed SIM behaviour at zero field and the slow relaxation of magnetization up to 8.0 K. PMID:27173026

  19. Preparation and use of crystalline bis-monoorganic phosphonate and phosphate salts of tetravalent metals

    DOEpatents

    Maya, L.

    1980-06-26

    A method of preparing and using the crystalline organic derivatives of the tetravalent metal phosphates and phosphonates provides for the contacting of an aqueous solution of a metal nitrate, with a solution of an organophosphorus acid for a period of time at room temperature that is sufficient for the formation of a metal phosphate product, and thereafter recovering said product. According to the invention, the product of the disclosed process is used in effecting analytical separations, such as ion exchange and chromatography.

  20. Chiral Vinylphosphonate and Phosphonate Analogues of the Immunosuppressive Agent FTY720

    PubMed Central

    Lu, Xuequan; Sun, Chaode; Valentine, William J.; E, Shuyu; Liu, Jianxiong; Tigyi, Gabor; Bittman, Robert

    2009-01-01

    The first enantioselective synthesis of chiral isosteric phosphonate analogues of FTY720 is described. One of these analogues, FTY720-(E)-vinylphosphonate (S)-5, but not its R enantiomer, elicited a potent anti-apoptotic effect in intestinal epithelial cells, suggesting that it exerts its action via the enantioselective activation of a receptor. (S)-5 failed to activate the sphingosine 1-phosphate type 1 (S1P1) receptor. PMID:19296586

  1. Thiol-ene and H-phosphonate-ene reactions for lipid modifications

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The addition of H-E (E= -SR, -P(O)(OR)2 or -P(O)R2) to the carbon-carbon double bonds in lipids is a way to create new materials: lubricants, additives, polymers. In the current chapter, the radical addition of thiols (E= SR) and H-phosphonates (E= P(O)(OR)2) will be reviewed in detail. The kinetics...

  2. Synthesis and proteinase inhibitory properties of diphenyl phosphonate analogues of aspartic and glutamic acids.

    PubMed

    Hamilton, R; Walker, B; Walker, B J

    1998-07-01

    The synthesis of diphenyl phosphonate analogues of aspartic and glutamic acid, and their inhibitory activity against S. aureus V8 protease and granzyme B, is described. The study has revealed difficulties with protecting group compatibility in the synthesis of these analogues. Two analogues, Acetyl. AspP (OPh)2 and Acetyl.GluP (OPh)2 were found to function as irreversible inactivators of V8 proteinase, yet exhibit no activity against granzyme B. PMID:9873408

  3. Origin, Utilization, and Recycling of Nucleosides in the Central Nervous System

    ERIC Educational Resources Information Center

    Ipata, Piero Luigi

    2011-01-01

    The brain relies on the salvage of preformed purine and pyrimidine rings, mainly in the form of nucleosides, to maintain its nucleotide pool in the proper qualitative and quantitative balance. The transport of nucleosides from blood into neurons and glia is considered to be an essential prerequisite to enter their metabolic utilization in the…

  4. Analysis of Nucleosides in Municipal Wastewater by Large-Volume Liquid Chromatography Tandem Mass Spectrometry

    PubMed Central

    Brewer, Alex J.; Lunte, Craig

    2015-01-01

    Nucleosides are components of both DNA and RNA, and contain either a ribose (RNA) or 2deoxyribose (DNA) sugar and a purine or pyrimidine base. In addition to DNA and RNA turnover, modified nucleosides found in urine have been correlated to a diminished health status associated with AIDS, cancers, oxidative stress and age. Nucleosides found in municipal wastewater influent are potentially useful markers of community health status, and as of now, remain uninvestigated. A method was developed to quantify nucleosides in municipal wastewater using large-volume injection, liquid chromatography, and mass spectrometry. Method accuracy ranged from 92 to 139% when quantified by using isotopically labeled internal standards. Precision ranged from 6.1 to 19% of the relative standard deviation. The method’s utility was demonstrated by the analysis of twenty-four hour composite wastewater influent samples that were collected over a week to investigate community nucleoside excretion. Nucleosides originating from RNA were more abundant that DNA over the study period, with total loads of nucleosides ranging from 2 to 25 kg/day. Given this relatively high amount of nucleosides found over the study period they present an attractive analyte for the investigation of community health. PMID:26322136

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

    PubMed Central

    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

  6. Visualizing nucleic acid metabolism using non-natural nucleosides and nucleotide analogs.

    PubMed

    Choi, Jung-Suk; Berdis, Anthony J

    2016-01-01

    Nucleosides and their corresponding mono-, di-, and triphosphates play important roles in maintaining cellular homeostasis. In addition, perturbations in this homeostasis can result in dysfunctional cellular processes that cause pathological conditions such as cancer and autoimmune diseases. This review article discusses contemporary research areas applying nucleoside analogs to probe the mechanistic details underlying the complexities of nucleoside metabolism at the molecular and cellular levels. The first area describes classic and contemporary approaches used to quantify the activity of nucleoside transporters, an important class of membrane proteins that mediate the influx and efflux of nucleosides and nucleobases. A focal point of this section is describing how biophotonic nucleosides are replacing conventional assays employing radiolabeled substrates to study the mechanism of these proteins. The second section describes approaches to understand the utilization of nucleoside triphosphates by cellular DNA polymerases during DNA synthesis. Emphasis here is placed on describing how novel nucleoside analogs such as 5-ethynyl-2'-deoxyuridine are being used to quantify DNA synthesis during normal replication as well as during the replication of damaged DNA. In both sections, seminal research articles relevant to these areas are described to highlight how these novel probes are improving our understanding of these biological processes. This article is part of a Special Issue entitled: Physiological Enzymology and Protein Functions. PMID:26004088

  7. Novel inhibitors of Mycobacterium tuberculosis growth based on modified pyrimidine nucleosides and their analogues

    NASA Astrophysics Data System (ADS)

    Shmalenyuk, E. R.; Kochetkov, S. N.; Alexandrova, L. A.

    2013-09-01

    The review summarizes data on the synthesis and antituberculosis activity of pyrimidine nucleoside derivatives and their analogues. Enzymes from M. tuberculosis as promising targets for prototypes of new-generation drugs are considered. Nucleosides as inhibitors of drug-resistant M. tuberculosis strains are characterized. The bibliography includes 101 references.

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

    PubMed Central

    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

  9. Nucleoside inhibitors of tick-borne encephalitis virus.

    PubMed

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

    2015-09-01

    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

  10. Nucleoside Inhibitors of Tick-Borne Encephalitis Virus

    PubMed Central

    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

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

    PubMed

    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

  12. Phase Behavior and Conductivity of Phosphonated Block Copolymers Containing Ionic Liquids

    NASA Astrophysics Data System (ADS)

    Jung, Ha Young; Kim, Sung Yeon; Park, Moon Jeong

    2015-03-01

    As the focus on proton exchange fuel cells continues to escalate in the era of alternative energy systems, the rational design of sulfonated polymers has emerged as a key technique for enhancing device efficiency. While the sulfonic acid group guarantees high proton conductivity of membranes under humidified conditions, the growing need for high temperature operation has discouraged their practical uses in fuel cells. In this respect, phosphonated polymers have drawn intensive attention in recent years owing to their self-dissociation ability. In this study, we have synthesized a set of phosphonated block copolymers, poly(styrenephosphonate-methylbutylene) (PSP- b - PMB), by varying phosphonation level (PL). A wide variety of self-assembled morphologies, i.e., disordered, lamellar, hexagonally perforated lamellae and hexagonally packed cylindrical phases, were observed with PL. Remarkably, upon comparing the morphology of PSP- b-PMB and that of sulfonated analog, we found distinctly dissimilar domain sizes at the same molecular weight and composition. A range of ionic liquids (ILs) were incorporated into the PSP- b-PMB block copolymers and their ion transport properties were examined. It has been revealed that the degree of confinement of ionic phases (domain size) impacts the ion mobility and proton dissociation efficiency of IL-containing polymers.

  13. Flower-like supramolecular self-assembly of phosphonic acid appended naphthalene diimide and melamine

    PubMed Central

    Bhosale, Rajesh S; Al Kobaisi, Mohammad; Bhosale, Sidhanath V.; Bhargava, Suresh; Bhosale, Sheshanath V.

    2015-01-01

    Diverse supramolecular assemblies ranging from nanometres to micrometers of small aromatic π-conjugated functional molecules have attracted enormous research interest in light of their applications in optoelectronics, chemosensors, nanotechnology, biotechnology and biomedicines. Here we study the mechanism of the formation of a flower-shaped supramolecular structure of phosphonic acid appended naphthalene diimide with melamine. The flower-shaped assembly formation was visualised by scanning electron microscope (SEM) and transmission electron microscopy (TEM) imaging, furthermore, XRD and DLS used to determined mode of aggregation. Characteristically, phosphonic acid-substituted at imide position of NDIs possess two important properties resulting in the formation of controlled flower-like nanostructures: (i) the aromatic core of the NDI which is designed to optimize the dispersive interactions (π-π stacking and van der Waals interactions) between the cores within a construct and (ii) phosphonic acid of NDI interact with malamine through molecular recognition i.e. strong hydrogen-bonding (H-bonding). We believe such arrangements prevent crystallization and favour the directional growth of flower-like nanostructure in 3D fashion. These works demonstrate that complex self-assembly can indeed be attained through hierarchical non-covalent interactions of two components. Furthermore, flower-like structures built from molecular recognition by these molecules indicate their potential in other fields if combined with other chemical entities. PMID:26416382

  14. Evaluation of 2'-hydroxyl protection in RNA-synthesis using the H-phosphonate approach.

    PubMed Central

    Rozners, E; Westman, E; Strömberg, R

    1994-01-01

    A number of different protecting groups were compared with respect to their usefulness for protection of 2'-hydroxyl functions during synthesis of oligoribonucleotides using the H-phosphonate approach. The comparison was between the t-butyldimethylsilyl (t-BDMSi), the o-chlorobenzoyl (o-CIBz), the tetrahydropyranyl (THP), the 1-(2-fluorophenyl)-4-methoxypiperidin-4-yl (Fpmp), the 1-(2-chloro-4-methylphenyl)-4-methoxypiperidin-4-yl (Ctmp), and the 1-(2-chloroethoxy)ethyl (Cee) protecting groups. All these groups were tested in synthesis of dodecamers, (Up)11U and (Up)11A, using 5'-O-(4-monomethoxytrityl) or (4,4'-dimethoxytrityl) uridine H-phosphonate building blocks carrying the respective 2'-protection. The performance of the t-BDMSi and o-CIBz derivatives were also compared in synthesis of (Up)19U. The most successful syntheses were clearly those where the t-butyldimethylsilyl group was used. The o-chlorobenzoyl group also gave satisfactory results but seems somewhat limited with respect to synthesis of longer oligomers. The results with all tested acetal derivatives (Fpmp, Ctmp, Cee, THP) were much less successful due to some accompanying cleavage of internucleotidic H-phosphonate functions during removal of 5'-O-protection (DMT). PMID:8127660

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

    PubMed

    Nguyen, Monique M; Al-Abdul-Wahid, M Sameer; Fontenot, Krystal R; Graves, Elena E; Chang, SeChin; Condon, Brian D; Grimm, Casey C; Lorigan, Gary A

    2015-01-01

    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. PMID:26096432

  16. Structure and Order of Phosphonic Acid-Based Self-Assembled Monolayers on Si(100)

    PubMed Central

    Dubey, Manish; Weidner, Tobias; Gamble, Lara J.; Castner, David G.

    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° and 45°, respectively. PMID:20735054

  17. Flower-like supramolecular self-assembly of phosphonic acid appended naphthalene diimide and melamine

    NASA Astrophysics Data System (ADS)

    Bhosale, Rajesh S.; Al Kobaisi, Mohammad; Bhosale, Sidhanath V.; Bhargava, Suresh; Bhosale, Sheshanath V.

    2015-09-01

    Diverse supramolecular assemblies ranging from nanometres to micrometers of small aromatic π-conjugated functional molecules have attracted enormous research interest in light of their applications in optoelectronics, chemosensors, nanotechnology, biotechnology and biomedicines. Here we study the mechanism of the formation of a flower-shaped supramolecular structure of phosphonic acid appended naphthalene diimide with melamine. The flower-shaped assembly formation was visualised by scanning electron microscope (SEM) and transmission electron microscopy (TEM) imaging, furthermore, XRD and DLS used to determined mode of aggregation. Characteristically, phosphonic acid-substituted at imide position of NDIs possess two important properties resulting in the formation of controlled flower-like nanostructures: (i) the aromatic core of the NDI which is designed to optimize the dispersive interactions (π-π stacking and van der Waals interactions) between the cores within a construct and (ii) phosphonic acid of NDI interact with malamine through molecular recognition i.e. strong hydrogen-bonding (H-bonding). We believe such arrangements prevent crystallization and favour the directional growth of flower-like nanostructure in 3D fashion. These works demonstrate that complex self-assembly can indeed be attained through hierarchical non-covalent interactions of two components. Furthermore, flower-like structures built from molecular recognition by these molecules indicate their potential in other fields if combined with other chemical entities.

  18. Phosphonate-Derived Nanoporous Metal Phosphates and Their Superior Energy Storage Application.

    PubMed

    Pramanik, Malay; Salunkhe, Rahul R; Imura, Masataka; Yamauchi, Yusuke

    2016-04-20

    Nanoporous nickel, aluminum, and zirconium phosphates (hereafter, abbreviated as NiP, AlP, and ZrP, respectively) with high surface areas and controlled morphology and crystallinity have been synthesized through simple calcination of the corresponding phosphonates. For the preparation of phosphonate materials, nitrilotris(methylene)triphosphonic acid (NMPA) is used as phosphorus source. The organic component in the phosphonate materials is thermally removed to form nanoporous structures in the final phosphate materials. The formation mechanism of nanoporous structures, as well as the effect of applied calcination temperatures on the morphology and crystallinity of the final phosphate materials, is carefully discussed. Especially, nanoporous NiP materials have a spherical morphology with a high surface area and can have great applicability as an electrode material for supercapacitors. It has been found that there is a critical effect of particle sizes, surface areas, and the crystallinities of NiP materials toward electrochemical behavior. Our nanoporous NiP material has superior specific capacitance, as compared to various phosphate nanomaterials reported previously. Excellent retention capacity of 97% is realized even after 1000 cycles, which can be ascribed to its high structural stability. PMID:27028363

  19. Computer-generated Model of Purine Nucleoside Phosphorylase (PNP)

    NASA Technical Reports Server (NTRS)

    1987-01-01

    Purine Nucleoside Phosphorylase (PNP) is an important target enzyme for the design of anti-cancer and immunosuppressive drugs. Bacterial PNP, which is slightly different from the human enzyme, is used to synthesize chemotherapuautic agents. Knowledge of the three-dimensional structure of the bacterial PNP molecule is useful in efforts to engineer different types of PNP enzymes, that can be used to produce new chemotherapeutic agents. This picture shows a computer model of bacterial PNP, which looks a lot like a display of colorful ribbons. Principal Investigator was Charles Bugg.

  20. Nucleoside derivatives from the marine-derived fungus Aspergillus versicolor.

    PubMed

    Chen, Min; Fu, Xiu-Mei; Kong, Chui-Jian; Wang, Chang-Yun

    2014-01-01

    Four nucleoside derivatives (1-4) were isolated from the fungus Aspergillus versicolor derived from the gorgonian Dichotella gemmacea collected in the South China Sea. Their structures were elucidated by comprehensive spectroscopic method of NMR and MS analysis. All isolated metabolites were evaluated for their cytotoxicity, antibacterial activity and lethality towards brine shrimp Artemia salina. Compounds 1/2 exhibited selective antibacterial activity against Staphylococcus epidermidis with an MIC value of 12.5 μM. It should be noted that 1 and 2, whose structures were listed in SciFinder Scholar, had no associated reference. This is the first report about their isolation, structure elucidation and biological activities. PMID:24670197

  1. Oligodeoxyribonucleotides containing 1,3-propanediol as nucleoside substitute.

    PubMed Central

    Seela, F; Kaiser, K

    1987-01-01

    1,3-Propanediol was protected with one dimethoxytrityl residue and converted into the methoxy- and cyanoethoxyphosphoramidites 2a and 2b, respectively. Solid-phase oligonucleotide synthesis, employing the phosphoramidite 2a resulted in the dodecamers d(CGCGAATTCGCG) (6-9), in which dA or dT residues were replaced by 1,3-propanediol. These oligomers showed a high tendency to form hairpins. Their phosphodiester bonds between the 3'-position of a nucleoside and the propanediol moiety was not cleaved by snake venom phosphodiesterase. PMID:3562246

  2. Synthesis of 5-Fluoroalkylated Pyrimidine Nucleosides via Negishi Cross-Coupling

    PubMed Central

    Chacko, Ann-Marie; Qu, Wenchao

    2014-01-01

    5-fluoroalkylated pyrimidine nucleosides (1) have potential as therapeutic agents and molecular imaging agents targeting HSV1-tk suicide gene therapy. Thus, straightforward preparation of 5-fluoroalkylated nucleoside derivatives has been developed. Reported herein are the first examples of Pd-catalyzed Negishi cross-coupling of 3-N-benzoyl-3′,5′-di-O-benzoyl-5-iodo-2′-deoxyuridine (2a) and 3-N-benzoyl-3′,5′-di-O-benzoyl-5-iodo-2′-deoxy-2′-fluoroarabinouridine (2b) with unactivated Csp3 fluoroalkylzinc bromides. This paper demonstrates the first synthesis of six 5-fluoroalkyl-2′-deoxy pyrimidine nucleoside derivatives with three to five methylene-chain lengths (5). Furthermore, this methodology has been extended to create a series of thirteen 5-alkyl substituted nucleosides, including the target nucleosides 5 and 5-silyloxypropyl and 5-cyanobutyl derivatives. PMID:18522415

  3. Theoretical understanding of two-photon-induced fluorescence of isomorphic nucleoside analogs.

    PubMed

    Samanta, Pralok K; Pati, Swapan K

    2015-04-21

    We use ab initio Density Functional Theory (DFT) and Time-dependent DFT (TDDFT) calculations for a detailed understanding of one-photon absorption (1PA) and two-photon absorption (2PA) cross sections of eight different nucleoside analogs. The results are compared and contrasted with the available experimental data. Our calculated results show that the low energy peaks in the absorption spectra mainly arise because of the π-π* electronic transition of the nucleoside analogs. The emission spectra of the nucleoside analogs are also calculated using TDDFT methods. The calculated absorption and emission spectra in the presence of a solvent follow the same trend as those found experimentally. Our results demonstrate that the nucleoside analogs show significantly different electronic and optical properties, although their bonding aspects towards Watson-Crick base pairing remain the same. We also derive the microscopic details of the origin of nonlinear optical properties of the nucleoside analogs. PMID:25785569

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

    PubMed

    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

  5. Synthesis, antiviral activity, cytotoxicity and cellular pharmacology of l-3'-azido-2',3'-dideoxypurine nucleosides.

    PubMed

    Zhang, Hong-Wang; Detorio, Mervi; Herman, Brian D; Solomon, Sarah; Bassit, Leda; Nettles, James H; Obikhod, Aleksandr; Tao, Si-Jia; Mellors, John W; Sluis-Cremer, Nicolas; Coats, Steven J; Schinazi, Raymond F

    2011-09-01

    Microwave-assisted optimized transglycosylation reactions were used to prepare eleven modified l-3'-azido-2',3'-dideoxypurine nucleosides. These l-nucleoside analogs were evaluated against HIV and hepatitis B virus. The l-3'-azido-2',3'-dideoxypurines nucleosides were metabolized to nucleoside 5'-triphosphates in primary human lymphocytes, but exhibited weak or no antiviral activity against HIV-1. The nucleosides were also inactive against HBV in HepG2 cells. Pre-steady state kinetic experiments demonstrated that the l-3'-azido-2',3'-dideoxypurine triphosphates could be incorporated by purified HIV-1 reverse transcriptase, although their catalytic efficiency (k(pol)/K(d)) of incorporation was low. Interestingly, a phosphoramidate prodrug of l-3'-azido-2',3'-dideoxyadenosine exhibited anti-HIV-1 activity without significant toxicity. PMID:21700368

  6. Versatile synthesis and biological evaluation of novel 3’-fluorinated purine nucleosides

    PubMed Central

    Ren, Hang; Hatala, Paul J; Stevens, William C; He, Baicheng

    2015-01-01

    Summary A unified synthetic strategy accessing novel 3'-fluorinated purine nucleoside derivatives and their biological evaluation were achieved. Novel 3’-fluorinated analogues were constructed from a common 3’-deoxy-3’-fluororibofuranose intermediate. Employing Suzuki and Stille cross-coupling reactions, fifteen 3’-fluororibose purine nucleosides 1–15 and eight 3’-fluororibose 2-chloro/2-aminopurine nucleosides 16–23 with various substituents at position 6 of the purine ring were efficiently synthesized. Furthermore, 3’-fluorine analogs of natural products nebularine and 6-methylpurine riboside were constructed via our convergent synthetic strategy. Synthesized nucleosides were tested against HT116 (colon cancer) and 143B (osteosarcoma cancer) tumor cell lines. We have demonstrated 3’-fluorine purine nucleoside analogues display potent tumor cell growth inhibition activity at sub- or low micromolar concentration. PMID:26734098

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

    PubMed

    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. PMID:27426410

  8. Cell Tracking Accuracy Measurement Based on Comparison of Acyclic Oriented Graphs.

    PubMed

    Matula, Pavel; Maška, Martin; Sorokin, Dmitry V; Matula, Petr; Ortiz-de-Solórzano, Carlos; Kozubek, Michal

    2015-01-01

    Tracking motile cells in time-lapse series is challenging and is required in many biomedical applications. Cell tracks can be mathematically represented as acyclic oriented graphs. Their vertices describe the spatio-temporal locations of individual cells, whereas the edges represent temporal relationships between them. Such a representation maintains the knowledge of all important cellular events within a captured field of view, such as migration, division, death, and transit through the field of view. The increasing number of cell tracking algorithms calls for comparison of their performance. However, the lack of a standardized cell tracking accuracy measure makes the comparison impracticable. This paper defines and evaluates an accuracy measure for objective and systematic benchmarking of cell tracking algorithms. The measure assumes the existence of a ground-truth reference, and assesses how difficult it is to transform a computed graph into the reference one. The difficulty is measured as a weighted sum of the lowest number of graph operations, such as split, delete, and add a vertex and delete, add, and alter the semantics of an edge, needed to make the graphs identical. The measure behavior is extensively analyzed based on the tracking results provided by the participants of the first Cell Tracking Challenge hosted by the 2013 IEEE International Symposium on Biomedical Imaging. We demonstrate the robustness and stability of the measure against small changes in the choice of weights for diverse cell tracking algorithms and fluorescence microscopy datasets. As the measure penalizes all possible errors in the tracking results and is easy to compute, it may especially help developers and analysts to tune their algorithms according to their needs. PMID:26683608

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

    PubMed

    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. PMID:25280628

  10. Cell Tracking Accuracy Measurement Based on Comparison of Acyclic Oriented Graphs

    PubMed Central

    Sorokin, Dmitry V.; Matula, Petr; Ortiz-de-Solórzano, Carlos; Kozubek, Michal

    2015-01-01

    Tracking motile cells in time-lapse series is challenging and is required in many biomedical applications. Cell tracks can be mathematically represented as acyclic oriented graphs. Their vertices describe the spatio-temporal locations of individual cells, whereas the edges represent temporal relationships between them. Such a representation maintains the knowledge of all important cellular events within a captured field of view, such as migration, division, death, and transit through the field of view. The increasing number of cell tracking algorithms calls for comparison of their performance. However, the lack of a standardized cell tracking accuracy measure makes the comparison impracticable. This paper defines and evaluates an accuracy measure for objective and systematic benchmarking of cell tracking algorithms. The measure assumes the existence of a ground-truth reference, and assesses how difficult it is to transform a computed graph into the reference one. The difficulty is measured as a weighted sum of the lowest number of graph operations, such as split, delete, and add a vertex and delete, add, and alter the semantics of an edge, needed to make the graphs identical. The measure behavior is extensively analyzed based on the tracking results provided by the participants of the first Cell Tracking Challenge hosted by the 2013 IEEE International Symposium on Biomedical Imaging. We demonstrate the robustness and stability of the measure against small changes in the choice of weights for diverse cell tracking algorithms and fluorescence microscopy datasets. As the measure penalizes all possible errors in the tracking results and is easy to compute, it may especially help developers and analysts to tune their algorithms according to their needs. PMID:26683608

  11. Na+ reabsorption in cultured rat epididymal epithelium via the Na+/nucleoside cotransporter.

    PubMed

    Leung, G P; Cheung, K H; Tse, C M; Wong, P Y

    2001-03-01

    The effect of nucleoside on Na+ reabsorption via Na+/nucleoside cotransporter in cultured rat epididymal epithelia was studied by short-circuit current (Isc) technique. Guanosine added apically stimulated Isc in a dose-dependent manner, with a median effective concentration (EC50) of 7 +/- 2 microM (mean +/- SEM). Removal of Na+ from the apical bathing solution or pretreatment with a nonspecific Na+/nucleoside cotransporter inhibitor, phloridzin, completely blocked the Isc response to guanosine. Moreover, the guanosine response was abolished by pretreatment of the tissue with ouabain, a Na+/K+-ATPase inhibitor, suggesting the involvement of Na+/nucleoside cotransporter on the apical side and Na+/K+-ATPase on the basolateral side in Na+ reabsorption. In contrast, the Isc response to guanosine was not affected after desensitization of purinoceptors by ATP. Addition of the Na+/K+/2Cl- symport inhibitor bumetanide to the basolateral side or the nonspecific Cl- channel blocker diphenylamine-2-carboxylate to the apical side showed no effect on the Isc response to guanosine, excluding stimulation of Cl- secretion by guanosine as the cause of the guanosine-induced Isc. The Isc response to purine nucleoside (guanosine and inosine) was much higher than that to pyrimidine nucleoside (thymidine and cytidine). Consistent with substrate specificity, results of reverse transcription-polymerase chain reaction revealed mRNA for concentrative nucleoside transporter (CNT2), which is a purine nucleoside-selective Na+/nucleoside cotransporter in the epididymis, but not for CNT1. It is suggested that the Na+/nucleoside cotransporter (i.e., CNT2) may be one of the elements involved in Na+ and fluid reabsorption in the epididymis, thereby providing an optimal microenvironment for the maturation and storage of spermatozoa. PMID:11207189

  12. Involvement of concentrative nucleoside transporter 1 in intestinal absorption of trifluorothymidine, a novel antitumor nucleoside, in rats.

    PubMed

    Okayama, Takashige; Yoshisue, Kunihiro; Kuwata, Keizo; Komuro, Masahito; Ohta, Shigeru; Nagayama, Sekio

    2012-02-01

    ααα-Trifluorothymidine (TFT), an anticancer nucleoside analog, is a potent thymidylate synthase inhibitor. TFT exerts its antitumor activity primarily by inducing DNA fragmentation after incorporation of the triphosphate form of TFT into the DNA. Although an oral combination of TFT and a thymidine phosphorylase inhibitor has been clinically developed, there is little information regarding TFT absorption. Therefore, we investigated TFT absorption in the rat small intestine. After oral administration of TFT in rats, more than 75% of the TFT was absorbed. To identify the uptake transport system, uptake studies were conducted by using everted sacs prepared from rat small intestines. TFT uptake was saturable, significantly reduced under Na(+)-free conditions, and strongly inhibited by the addition of an endogenous pyrimidine nucleoside. From these results, we suggested the involvement of concentrative nucleoside transporters (CNTs) in TFT absorption into rat small intestine. In rat small intestines, the mRNAs coding for rat CNT1 (rCNT1) and rCNT2, but not for rCNT3, were predominantly expressed. To investigate the roles of rCNT1 and rCNT2 in TFT uptake, we conducted uptake assays by using Xenopus laevis oocytes injected with rCNT1 complementary RNA (cRNA) and rCNT2 cRNA. TFT uptake by X. laevis oocytes injected with rCNT1 cRNA, and not rCNT2 cRNA, was significantly greater than that by water-injected oocytes. In addition, in situ single-pass perfusion experiments performed using rat jejunum regions showed that thymidine, a substrate for CNT1, strongly inhibited TFT uptake. In conclusion, TFT is absorbed via rCNT1 in the intestinal lumen in rats. PMID:22076553

  13. The use of functionalized monoalkyl phosphates and phosphonates in the colloidal processing of oxide ceramic powders

    NASA Astrophysics Data System (ADS)

    Radsick, Timothy Carl

    The purpose of this study was to develop phosphorous-based chemicals that could be used to modify the interparticle pair potential of several oxide ceramic particles, thereby enabling their use in colloidal processing schemes. Several procedures for the synthesis of 11-12 carbon alpha,o-functionalized monoalkyl phosphates and phosphonates were developed. Because of its simplicity and its use of mild reagents, a procedure based on the Michaelis-Arbuzov rearrangement was selected to produce the bulk of the chemicals used in this study. Carboxyl- and hydroxyl-terminated monoalkyl phosphonates were adsorbed onto alumina and zirconia powders using either aqueous-based or solvent-based methods to produce a monolayer of "brushlike" steric molecules. In the aqueous-based methods, powders were processed at pH values below their isoelectric point in order to produce a positive charge on the powder, thereby attracting the negatively charged phosphate or phosphonate group onto the powder surface to form the steric monolayer. In solvent-based methods, powder was suspended in an acetone solution of the phosphonates, heated at reflux, washed, dried and heat treated at 120°C under vacuum. The zeta potential of the coated powders was measured to quantify the degree of steric layer adsorption and the shift in the isoelectric point. Slurries of coated alumina and zirconia were prepared having 20 vol % powder. Rheological behavior was studied by measuring viscosity as a function of shear rate for slurries of various pH values and counterion concentrations. Slurries with powder processed via the solvent method were the least sensitive to changes in slurry pH and were straightforward to prepare. It is thought that the solvent-based coating procedure produced a stronger, multi-dentate powder-phosphonate bond than that of the aqueous-based procedure. Dispersed and coagulated slurries were able to be prepared over a wide pH range, including at the isoelectric point of the uncoated powders

  14. Acyclic CB[n]-Type Molecular Containers: Effect of Solubilizing Group on their Function as Solubilizing Excipients

    PubMed Central

    Zhang, Ben; Zavalij, Peter Y.; Isaacs, Lyle

    2014-01-01

    We report the synthesis and x-ray crystal structures of three acyclic CB[n]-type molecular containers (2a, 2h, 2f) that differ in the charge on their solubilizing groups (SO3−, OH, NH3+). The x-ray crystal structures of compounds 2h and 2f reveal a self-folding of the ArOCH2CH2X wall into the cavity driven by π–π interactions, H-bonds and ion-dipole interactions. The need to reverse this self-folding phenomenon upon guest binding decreases the affinity of 2h and 2f toward cationic guests in water relative to 2a as revealed by direct 1H NMR and UV/Vis titrations as well as UV/Vis competition experiments. We determined the pKa of 6-aminocoumarin 7 (pKa = 3.6) on its own and in the presence anionic, neutral, and cationic hosts (2a: pKa = 4.9; 2h: pKa = 4.1; 2f, pKa = 3.4) which reflect in part the relevance of direct ion-ion interactions between the arms of the host and the guest toward the recognition properties of acyclic CB[n]-type containers. Finally, we showed that the weaker binding affinities measured for neutral and positively charged hosts 2h and 2f compared to anionic 2a results in a decreased ability to act as solubilizing agents for either cationic (tamoxifen), neutral (17α–ethynylestradiol), or anionic (indomethacin) drugs in water. The results establish that acyclic CB[n] compounds that bear anionic solubilizing groups are most suitable for development as general purpose solubilizing excipients for insoluble pharmaceutical agents. PMID:24595500

  15. Cladribine Analogues via O6-(Benzotriazolyl) Derivatives of Guanine Nucleosides

    PubMed Central

    Satishkumar, Sakilam; Vuram, Prasanna K.; Relangi, Siva Subrahmanyam; Gurram, Venkateshwarlu; Zhou, Hong; Kreitman, Robert J.; Montemayor, Michelle M. Martínez; Yang, Lijia; Kaliyaperumal, Muralidharan; Sharma, Somesh; Pottabathini, Narender; Lakshman, Mahesh K.

    2016-01-01

    Cladribine, 2-chloro-2′-deoxyadenosine, is a highly efficacious clinically used nucleoside for the treatment of hairy cell leukemia. It is also being evaluated against other lymphoid malignancies and has been a molecule of interest for well over half a century. In continuation of our interest on the amide bond-activation in purine nucleosides via the use of (benzotriazol-1yl-oxy)tris(dimethylamino)phosphonium hexafluorophosphate, we have evaluated the use of O6-(benzotriazol-1-yl)-2′-deoxyguanosine as a potential precursor to cladribine and its analogues. These compounds, after appropriate deprotection, were assessed for their biological activities and the data are presented herein. Against hairy cell leukemia (HCL), T-cell lymphoma (TCL), and chronic lymphocytic leukemia (CLL) cladribine was the most active against all. The bromo analogue of cladribine showed comparable activity to the ribose analogue of cladribine against HCL, but was more active against TCL and CLL. The bromo ribo analogue of cladribine possessed activity, but was least active among the C6-NH2-containing compounds. Substitution with alkyl groups at the exocyclic amino group appears detrimental to activity, and only the C6 piperidinyl cladribine analogue demonstrated any activity. Against adenocarcinoma MDA-MB-231 cells, only cladribine and its ribose analogue were most active. PMID:26556315

  16. Kinetic and biochemical characterization of Trypanosoma evansi nucleoside triphosphate diphosphohydrolase.

    PubMed

    Weiss, Paulo Henrique Exterchoter; Batista, Franciane; Wagner, Glauber; Magalhães, Maria de Lourdes Borba; Miletti, Luiz Claudio

    2015-06-01

    Nucleoside triphosphate diphospho-hydrolases (NTPDases) catalyze the hydrolysis of several nucleosides tri and diphosphate playing major roles in eukaryotes including purinergic signaling, inflammation, hemostasis, purine salvage and host-pathogen interactions. These enzymes have been recently described in parasites where several evidences indicated their involvement in virulence and infection. Here, we have investigated the presence of NTPDase in the genome of Trypanosoma evansi. Based on the genomic sequence from Trypanosoma brucei, we have amplified an 1812 gene fragment corresponding to the T. evansi NTPDase gene. The protein was expressed in the soluble form and purified to homogeneity and enzymatic assays were performed confirming the enzyme identity. Kinetic parameters and substrate specificity were determined. The dependence of cations on enzymatic activity was investigated indicating the enzyme is stimulated by divalent cations and carbohydrates but inhibited by sodium. Bioinformatic analysis indicates the enzyme is a membrane bound protein facing the extracellular side of the cell with 98% identity to the T. brucei homologous NTPDase gene. PMID:25819299

  17. Adenylate kinase complements nucleoside diphosphate kinase deficiency in nucleotide metabolism.

    PubMed Central

    Lu, Q; Inouye, M

    1996-01-01

    Nucleoside diphosphate (NDP) kinase is a ubiquitous nonspecific enzyme that evidently is designed to catalyze in vivo ATP-dependent synthesis of ribo- and deoxyribonucleoside triphosphates from the corresponding diphosphates. Because Escherichia coli contains only one copy of ndk, the structural gene for this enzyme, we were surprised to find that ndk disruption yields bacteria that are still viable. These mutant cells contain a protein with a small amount NDP kinase activity. The protein responsible for this activity was purified and identified as adenylate kinase. This enzyme, also called myokinase, catalyzes the reversible ATP-dependent synthesis of ADP from AMP. We found that this enzyme from E. coli as well as from higher eukaryotes has a broad substrate specificity displaying dual enzymatic functions. Among the nucleoside monophosphate kinases tested, only adenylate kinase was found to have NDP kinase activity. To our knowledge, this is the first report of NDP kinase activity associated with adenylate kinase. Images Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 Fig. 7 PMID:8650159

  18. Lethal Mutagenesis of HIV with Mutagenic Nucleoside Analogs

    NASA Astrophysics Data System (ADS)

    Loeb, Lawrence A.; Essigmann, John M.; Kazazi, Farhad; Zhang, Jue; Rose, Karl D.; Mullins, James I.

    1999-02-01

    The human immunodeficiency virus (HIV) replicates its genome and mutates at exceptionally high rates. As a result, the virus is able to evade immunological and chemical antiviral agents. We tested the hypothesis that a further increase in the mutation rate by promutagenic nucleoside analogs would abolish viral replication. We evaluated deoxynucleoside analogs for lack of toxicity to human cells, incorporation by HIV reverse transcriptase, resistance to repair when incorporated into the DNA strand of an RNA\\cdot DNA hybrid, and mispairing at high frequency. Among the candidates tested, 5-hydroxydeoxycytidine (5-OH-dC) fulfilled these criteria. In seven of nine experiments, the presence of this analog resulted in the loss of viral replicative potential after 9-24 sequential passages of HIV in human CEM cells. In contrast, loss of viral replication was not observed in 28 control cultures passaged in the absence of the nucleoside analog, nor with other analogs tested. Sequence analysis of a portion of the HIV reverse transcriptase gene demonstrated a disproportionate increase in G -> A substitutions, mutations predicted to result from misincorporation of 5-OH-dC into the cDNA during reverse transcription. Thus, "lethal mutagenesis" driven by the class of deoxynucleoside analogs represented by 5-OH-dC could provide a new approach to treating HIV infections and, potentially, other viral infections.

  19. Amino acids of the Murchison meteorite. II - Five carbon acyclic primary beta-, gamma-, and delta-amino alkanoic acids

    NASA Technical Reports Server (NTRS)

    Cronin, J. R.; Pizzarello, S.; Yuen, G. U.

    1985-01-01

    The five-carbon acyclic primary beta, gamma, and delta amino alkanoic acids of the Murchison meteorite are studied using gas chromatography-mass spectrometry and ion exchange chromatography. The chromatograms reveal that alpha is the most abundant monoamino alkanoic acid followed by gamma and beta, and an exponential increase in the amount of amino acid is observed as the carbon number increases in the homologous series. The influence of frictional heating, spontaneous thermal decomposition, and radiation of the synthesis of amino acids is examined. The data obtained support an amino acid synthesis process involving random combination of single-carbon precursors.

  20. Radiolabeled nucleoside analogs in cancer diagnosis and therapy.

    PubMed

    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

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

    SciTech Connect

    Guan, Lei; Wang, Ying

    2015-08-15

    A novel cobalt phosphonate, [Co(HL)(H{sub 2}O){sub 3}]{sub n} (1) (L=N(CH{sub 2}PO{sub 3}H){sub 3}{sup 3−}) 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 CoO{sub 6} 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.

  2. Transport of physiological nucleosides and anti-viral and anti-neoplastic nucleoside drugs by recombinant Escherichia coli nucleoside-H(+) cotransporter (NupC) produced in Xenopus laevis oocytes.

    PubMed

    Loewen, Shaun K; Yao, Sylvia Y M; Slugoski, Melissa D; Mohabir, Nadira N; Turner, Raymond J; Mackey, John R; Weiner, Joel H; Gallagher, Maurice P; Henderson, Peter J F; Baldwin, Stephen A; Cass, Carol E; Young, James D

    2004-01-01

    The recently identified human and rodent plasma membrane proteins CNT1, CNT2 and CNT3 belong to a gene family (CNT) that also includes the bacterial nucleoside transport protein NupC. Heterologous expression in Xenopus oocytes has established that CNT1-3 correspond functionally to the three major concentrative nucleoside transport processes found in human and other mammalian cells (systems cit, cif and cib, respectively) and mediate Na(+) - linked uptake of both physiological nucleosides and anti-viral and anti-neoplastic nucleoside drugs. Here, one describes a complementary Xenopus oocyte transport study of Escherichia coli NupC using the plasmid vector pGEM-HE in which the coding region of NupC was flanked by 5'- and 3'-untranslated sequences from a Xenopus beta-globin gene. Recombinant NupC resembled human (h) and rat (r) CNT1 in nucleoside selectivity, including an ability to transport adenosine and the chemotherapeutic drugs 3'-azido-3'-deoxythymidine (AZT), 2',3'- dideoxycytidine (ddC) and 2'-deoxy-2',2'-difluorocytidine (gemcitabine), but also interacted with inosine and 2',3'- dideoxyinosine (ddl). Apparent affinities were higher than for hCNT1, with apparent K(m) values of 1.5-6.3 microM for adenosine, uridine and gemcitabine, and 112 and 130 microM, respectively, for AZT and ddC. Unlike the relatively low translocation capacity of hCNT1 and rCNT1 for adenosine, NupC exhibited broadly similar apparent V(max) values for adenosine, uridine and nucleoside drugs. NupC did not require Na(+) for activity and was H(+) - dependent. The kinetics of uridine transport measured as a function of external pH were consistent with an ordered transport model in which H(+) binds to the transporter first followed by the nucleoside. These experiments establish the NupC-pGEM-HE/oocyte system as a useful tool for characterization of NupC-mediated transport of physiological nucleosides and clinically relevant nucleoside therapeutic drugs. PMID:14668133

  3. DEGRADATION OF NITRILOTRIS (METHYLENEPHOSPHONIC ACID) AND RELATED (AMINO) PHOSPHONATE CHELATING AGENTS IN THE PRESENCE OF MANGANESE AND MOLECULAR OXYGEN. (R826376)

    EPA Science Inventory

    Phosphonates are used in an increasing variety of industrial and household
    applications including cooling waters systems, oil production, textile industry,
    and detergents. Phosphonates are not biodegraded during wastewater treatment but
    instead are removed by adsor...

  4. Synthesis and comparison of the biological activity of monocyclic phosphonate, difluorophosphonate and phosphate analogs of the natural AChE inhibitor cyclophostin.

    PubMed

    Martin, Benjamin P; Vasilieva, Elena; Dupureur, Cynthia M; Spilling, Christopher D

    2015-12-15

    New monocyclic phosphate, phosphonate and difluorophosphonate analogs of the natural AChE inhibitor cyclophostin were synthesized and their activity toward human AChE examined. Surprisingly, the phosphate, phosphonate, and difluorophosphonate analogs all showed diminished activity when compared with the natural product. PMID:26585276

  5. Functionalization of 2H-1,2,3-Triazole C-Nucleoside Template via N(2) Selective Arylation.

    PubMed

    Lopes, Alexandra Basilio; Wagner, Patrick; de Souza, Rodrigo Octavio Mendonça Alves; Germain, Nadège Lubin; Uziel, Jacques; Bourguignon, Jean-Jacques; Schmitt, Martine; Miranda, Leandro S M

    2016-06-01

    C-Nucleosides are an underexplored and important class of nucleosides with antiviral and anticancer activity. In addition, triazole heterocycles are well employed as a strategy to modify nucleobase in nucleoside analogues, although rare examples were described for triazoyl C-nucleosides. N(2)-Aryl-1,2,3-triazole C-nucleoside compounds that could be obtained by selective 1,2,3-triazole heterocycle N(2) arylation in 1-β-d-ribofuranosyl-2H-1,2,3-triazole substrate were designed in this study. The optimized condition used AdBrettPhos/[PdCl(allyl)]2 as the catalyst system. This transformation was accomplished by aryl halides bearing an electron donor and withdrawing groups, as well as by heterocyclic halides in good to excellent yields. The transformation developed in this study represents a significant contribution to the nucleoside field, once it allows for the synthesis of unexplored scaffolds through selective functionalization of triazole nucleosides. PMID:27166644

  6. Modified nucleosides as biomarkers for early cancer diagnose in exposed populations.

    PubMed

    Seidel, Annerose; Seidel, Peter; Manuwald, Olaf; Herbarth, Olf

    2015-07-01

    There is increasing worldwide interest in developing of markers for tumor diagnosis and identification of individuals who are at high cancer risk. Cancer, like other diseases accompanied by metabolic disorders, causes characteristic effects on cell turnover rate, activity of modifying enzymes, and RNA/DNA modifications. This results in an increased excretion of modified nucleosides in cancer patients. Therefore, for many years modified nucleosides have been suggested as tumor markers. The aim of the study was to elucidate further the usefulness of urinary nucleosides as possible markers at early detection of cancer in persons which are exposed against tumor promoting influences during their working life. Uranium miners are exposed to many kinds of pollutants that can cause health damage even lead to carcinogenesis. We analyzed modified nucleosides in urine samples from 92 miners who are at high risk for lung cancer to assess the levels of nucleosides by a multilayer perceptron (MLP) classifier - a neural network model. Eighteen nucleosides/metabolites were detected with reversed-phase high-pressure liquid chromatography (RP-HPLC). A valid set of urinary metabolites were selected and multivariate statistical technique of multilayer perceptron neural network were applied. In a previous study, MLP shows a sensitivity and specificity of 97 and 85%, respectively. MLP classification including the most relevant markers/nucleosides clearly demonstrates the elevation of RNA metabolism in miners, which is associated with possible malignant disease. We found that there were 30 subjects with early health disorders among 92 uranium workers based on MLP technique using modified nucleosides. The combination of RP-HPLC analysis of modified nucleosides and subsequent MLP analyses represents a promising tool for the development of a non-invasive prediction system and may assist in developing management and surveillance procedures. PMID:24615900

  7. Selective synthesis of substituted pyrrole-2-phosphine oxides and -phosphonates from 2H-azirines and enolates from acetyl acetates and malonates.

    PubMed

    Palacios, Francisco; Ochoa de Retana, Ana M; Vélez del Burgo, Ander

    2011-11-18

    A simple and efficient selective synthesis of 1H-pyrrole-2-phosphine oxides 3 and -phosphonates 7 by addition of enolates derived from acetyl acetates to 2H-azirinylphosphine oxide 1 and -phosphonate 6 is reported. Nucleophilic addition of enolates derived from diethyl malonate to 2H-azirines 1 and 6 led to the formation of functionalized 2-hydroxy-1H-pyrrole-5-phosphine oxide 9 and -phosphonate 10, while vinylogous α-aminoalkylphosphine oxides 14 and -phosphonate 15 may be obtained from azirines and the enolate derived from diethyl 2-phenylmalonate. Ring closure of vinylogous derivatives 14 and 15 in the presence of base led to the formation of 1,5-dihydro-3-pyrrolin-2-ones containing a phosphine oxide 17 or a phosphonate group 18. PMID:21999212

  8. The Effect of Acyclic Retinoid on the Metabolomic Profiles of Hepatocytes and Hepatocellular Carcinoma Cells

    PubMed Central

    Qin, Xian-Yang; Wei, Feifei; Tanokura, Masaru; Ishibashi, Naoto; Shimizu, Masahito; Moriwaki, Hisataka; Kojima, Soichi

    2013-01-01

    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 identified in

  9. Synthesis of cycloalkyl substituted purine nucleosides via a metal-free radical route.

    PubMed

    Wang, Dong-Chao; Xia, Ran; Xie, Ming-Sheng; Qu, Gui-Rong; Guo, Hai-Ming

    2016-05-01

    An efficient route to synthesize cycloalkyl substituted purine nucleosides was developed. This metal-free C-H activation was accomplished by a tBuOOtBu initiated radical reaction. By adjusting the amount of tBuOOtBu and reaction time, the selective synthesis of C6-monocycloalkyl or C6,C8-dicycloalkyl substituted purine nucleosides could be realized. Furthermore, uracil and related nucleosides were also suitable substrates, giving the C5-cyclohexyl substituted uracil derivatives in good yields with excellent regioselectivities. PMID:27101306

  10. Synthesis of α-l-Threofuranosyl Nucleoside Triphosphates (tNTPs)

    PubMed Central

    Zou, Keyong; Horhota, Allen; Yu, Biao; Szostak, Jack W.

    2005-01-01

    The α-l-threofuranosyl nucleoside triphosphates of T, G, and D (tTTP, tGTP, and tDTP) were synthesized from the described 2‘-O-DMT-protected derivatives using the Eckstein method, while the corresponding C derivative (tCTP) was prepared from the 2‘-O-acetyl derivative. The prepared α-l-threofuranosyl nucleoside triphosphates, despite being one carbon shorter than the native 2‘-deoxyfuranosyl nucleoside triphosphates, are effective substrates for selected DNA polymerases. PMID:15816733

  11. The search for nucleoside/nucleotide analog inhibitors of dengue virus.

    PubMed

    Chen, Yen-Liang; Yokokawa, Fumiaki; Shi, Pei-Yong

    2015-10-01

    Nucleoside analogs represent the largest class of antiviral agents and have been actively pursued for potential therapy of dengue virus (DENV) infection. Early success in the treatment of human immunodeficiency virus (HIV) infection and the recent approval of sofosbuvir for chronic hepatitis C have provided proof of concept for this class of compounds in clinics. Here we review (i) nucleoside analogs with known anti-DENV activity; (ii) challenges of the nucleoside antiviral approach for dengue; and (iii) potential strategies to overcome these challenges. This article forms part of a symposium in Antiviral Research on flavivirus drug discovery. PMID:26241002

  12. Identification of a novel compound that inhibits osteoclastogenesis by suppressing nucleoside transporters.

    PubMed

    Katsuyama, Shun; Sugino, Kumi; Sasazawa, Yukiko; Nakano, Yoshihiko; Aono, Harumi; Morishita, Keisuke; Kawatani, Makoto; Umezawa, Kazuo; Osada, Hiroyuki; Simizu, Siro

    2016-04-01

    We screened small-molecule compounds that inhibit osteoclast differentiation to find new anti-osteoporosis agents and found that a novel compound, SUKU-1, suppressed osteoclastogenesis. We also synthesized 38 derivatives of SUKU-1 and discovered that nine of them had inhibitory effects on osteoclastogenesis and that SUKU-33 was the most potent inhibitor. Next, we investigated the mechanisms by which SUKU-33 suppressed osteoclast differentiation. By measuring the uptake of [(3) H]-uridine in cells, we found that SUKU-33 suppressed both equilibrative nucleoside transporters and concentrative nucleoside transporters. These results suggest that SUKU-33 inhibits osteoclast differentiation by suppressing nucleoside transporters. PMID:27001232

  13. Application of crystallographic and modeling methods in the design of purine nucleoside phosphorylase inhibitors.

    PubMed Central

    Ealick, S E; Babu, Y S; Bugg, C E; Erion, M D; Guida, W C; Montgomery, J A; Secrist, J A

    1991-01-01

    Competitive inhibitors of the salvage pathway enzyme purine-nucleoside phosphorylase (purine-nucleoside:orthophosphate ribosyltransferase, EC 2.4.2.1) have been designed by using the three-dimensional structure of the enzyme as determined by x-ray crystallography. The process was an iterative one that utilized interactive computer graphics, Monte Carlo-based conformational searching, energy minimization, and x-ray crystallography. The proposed compounds were synthesized and tested by an in vitro assay. Among the compounds designed and synthesized are the most potent competitive inhibitors of purine nucleoside phosphorylase thus far reported. Images PMID:1763067

  14. An Efficient Protection-Free One-Pot Chemical Synthesis of Modified Nucleoside-5'-Triphosphates.

    PubMed

    Shanmugasundaram, Muthian; Senthilvelan, Annamalai; Xiao, Zejun; Kore, Anilkumar R

    2016-07-01

    A simple, reliable, and an efficient "one-pot, three step" chemical method for the synthesis of modified nucleoside triphosphates such as 5-methylcytidine-5'-triphosphate (5-MeCTP), pseudouridine-5'-triphosphate (pseudoUTP) and N(1)-methylpseudouridine-5'-triphosphate (N(1)-methylpseudoUTP) starting from the corresponding nucleoside is described. The overall reaction involves the monophosphorylation of nucleoside, followed by the reaction with pyrophosphate and subsequent hydrolysis of the cyclic intermediate to furnish the corresponding NTP in moderate yields with high purity (>99.5%). PMID:27159048

  15. Discovery of the antibiotic phosacetamycin via a new mass spectrometry-based method for phosphonic acid detection

    PubMed Central

    Evans, Bradley S.; Zhao, Changming; Gao, Jiangtao; Evans, Courtney M.; Ju, Kou-San; Doroghazi, James R.; van der Donk, Wilfred A.; Kelleher, Neil L.; Metcalf, William W.

    2013-01-01

    Naturally occurring phosphonates such as phosphinothricin (Glufosinate, a commercially used herbicide) and fosfomycin (Monurol, a clinically used antibiotic) have proved to be potent and useful biocides. Yet this class of natural products is still an under explored family of secondary metabolites. Discovery of the biosynthetic pathways responsible for the production of these compounds has been simplified by using gene based screening approaches, but detection and identification of the natural products the genes produce has been hampered by a lack of high-throughput methods for screening potential producers under various culture conditions. Here we present an efficient mass-spectrometric method for the selective detection of natural products containing phosphonate and phosphinate functional groups. We have used this method to identify a new phosphonate metabolite, phosacetamycin, whose structure, biological activity, and biosynthetic gene cluster are reported. PMID:23474169

  16. Zirconium(IV)-Benzene Phosphonate Coordination Polymers: Lanthanide and Actinide Extraction and Thermal Properties.

    PubMed

    Luca, Vittorio; Tejada, Juan J; Vega, Daniel; Arrachart, Guilhem; Rey, Cyrielle

    2016-08-15

    Coordination polymers with different P/(Zr + P) molar ratios were prepared by combining aqueous solutions of Zr(IV) and benzenephosphonate derivatives. 1,3,5-Benzenetrisphosphonic acid (BTP) as well as phosphonocarboxylate derivatives in which carboxylate substitutes one or two of the phosphonate groups were chosen as the building blocks. The precipitates obtained on combining the two solutions were not X-ray amorphous but rather were indicative of poorly ordered materials. Hydrothermal treatment did not alter the structure of the materials produced but did result in improved crystalline order. The use of HF as a mineralizing agent during hydrothermal synthesis resulted in the crystallization of at least three relatively crystalline phases whose structure could not be determined owing to the complexity of the diffraction patterns. Gauging from the similarity of the diffraction patterns of all the phases, the poorly ordered precipitates and crystalline materials appeared to have similar underlying structures. The BTP-based zirconium phosphonates all showed a higher selectivity for lanthanides and thorium compared with cations such as Cs(+), Sr(2+), and Co(2+). Substitution of phosphonate groups by carboxylate groups did little to alter the pattern of selectivity implying that selectivity in the system was entirely determined by the -POH group with little influence from the -COOH groups. Samples with the highest phosphorus content showed the highest extraction efficiencies for lanthanide elements, especially the heavy lanthanides such as Dy(3+) and Ho(3+) with separation factors of around four with respect to La(3+). In highly acid solutions (4 M HNO3) there was a pronounced variation in extraction efficiency across the lanthanide series. In situ, nonambient diffraction was performed on ZrBTP-0.8 loaded with Th, Ce, and a complex mixture of lanthanides. In all cases the crystalline Zr2P2O7 pyrophosphate phase was formed at ∼800 °C demonstrating the versatility of

  17. Attenuation of nucleoside and anti-cancer nucleoside analog drug uptake in prostate cancer cells by Cimicifuga racemosa extract BNO-1055.

    PubMed

    Dueregger, Andrea; Guggenberger, Fabian; Barthelmes, Jan; Stecher, Günther; Schuh, Markus; Intelmann, Daniel; Abel, Gudrun; Haunschild, Jutta; Klocker, Helmut; Ramoner, Reinhold; Sampson, Natalie

    2013-11-15

    This study aimed to investigate the mechanisms underlying the anti-proliferative effects of the ethanolic Cimicifuga racemosa extract BNO-1055 on prostate cells and evaluate its therapeutic potential. BNO-1055 dose-dependently attenuated cellular uptake and incorporation of thymidine and BrdU and significantly inhibited cell growth after long-time exposure. Similar results were obtained using saponin-enriched sub-fractions of BNO-1055. These inhibitory effects of BNO-1055 could be mimicked using pharmacological inhibitors and isoform-specific siRNAs targeting the equilibrative nucleoside transporters ENT1 and ENT2. Moreover, BNO-1055 attenuated the uptake of clinically relevant nucleoside analogs, e.g. the anti-cancer drugs gemcitabine and fludarabine. Consistent with inhibition of the salvage nucleoside uptake pathway BNO-1055 potentiated the cytotoxicity of the de novo nucleotide synthesis inhibitor 5-FU without significantly altering its uptake. Collectively, these data show for the first time that the anti-proliferative effects of BNO-1055 result from hindered nucleoside uptake due to impaired ENT activity and demonstrate the potential therapeutic use of BNO-1055 for modulation of nucleoside transport. PMID:23972793

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

    NASA Astrophysics Data System (ADS)

    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.

  19. In Vivo Bone-Targeting of Bis(phosphonate)-Conjugated Double Helical RNA Monitored by Positron Emission Tomography.

    PubMed

    Jadhav, Satish; Käkelä, Meeri; Bourgery, Matthieu; Rimpilä, Kiira; Liljenbäck, Heidi; Siitonen, Riikka; Mäkilä, Jussi; Laitala-Leinonen, Tiina; Poijärvi-Virta, Päivi; Lönnberg, Harri; Roivainen, Anne; Virta, Pasi

    2016-07-01

    A bis(phosphonate) conjugate of 2'-O-methyl oligoribonucleotide (microRNA-21) was synthesized and used as a bone-targeting carrier in the systemic delivery of a (68)Ga-1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA)-chelated 2'-O-methyl oligoribonucleotide (anti-microRNA-21). The whole-body biodistribution of the double helical RNA was monitored by positron emission tomography (PET), which verified the expected bis(phosphonate)-induced bone accumulation in healthy rats. PMID:27218688

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

    PubMed Central

    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

  1. Tunneling Spectroscopy Studies of Urea, Thiourea, and Selected Phosphonate Molecules Adsorbed on Aluminum Oxide

    NASA Astrophysics Data System (ADS)

    Crowder, Charles D.

    -O-(H) stretching frequencies in the tunneling spectra indicated that the phosphonates bond to the aluminum oxide surface through the phosphonate group. MPA did not react with the aluminum oxide layer in the same fashion as the other phosphonate compounds, and its tunneling spectrum was not obtained. It can be concluded that MPA is a very poor hydration inhibitor. Theoretical intensity calculations were not attempted on the phosphonate compounds because adequate vibrational analyses have not been performed for these molecules.

  2. Phosphonate derivatives of tetraazamacrocycles as new inhibitors of protein tyrosine phosphatases.

    PubMed

    Kobzar, Oleksandr L; Shevchuk, Michael V; Lyashenko, Alesya N; Tanchuk, Vsevolod Yu; Romanenko, Vadim D; Kobelev, Sergei M; Averin, Alexei D; Beletskaya, Irina P; Vovk, Andriy I; Kukhar, Valery P

    2015-07-21

    α,α-Difluoro-β-ketophosphonated derivatives of tetraazamacrocycles were synthesized and found to be potential inhibitors of protein tyrosine phosphatases. N-Substituted conjugates of cyclam and cyclen with bioisosteric phosphonate groups displayed good activities toward T-cell protein tyrosine phosphatase with IC50 values in the micromolar to nanomolar range and showed selectivity over PTP1B, CD45, SHP2, and PTPβ. Kinetic studies indicated that the inhibitors can occupy the region of the active site of TC-PTP. This study demonstrates a new approach which employs tetraazamacrocycles as a molecular platform for designing inhibitors of protein tyrosine phosphatases. PMID:26058329

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

    PubMed

    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

  4. Inorganic resist materials based on zirconium phosphonate for atomic force microscope lithography

    NASA Astrophysics Data System (ADS)

    Kang, Mankyu; Kim, Seonae; Jung, JinHyuck; Kim, Heebom; Shin, Inkyun; Jeon, Chanuk; Lee, Haiwon

    2014-03-01

    New inorganic resist materials based on metal complexes were investigated for atomic force microscope (AFM) lithography. Phosphoric acids are good for self-assembly because of their strong binding energy. In this work, zirconium phosphonate system are newly synthesized for spin-coatable materials in aqueous solutions and leads to negative tone pattern for improving line edge roughness. Low electron exposure by AFM lithography could generate a pattern by electrochemical reaction and cross-linking of metal-oxo complexes. It has been reported that the minimum pattern results are affected by lithographic speed, and the applied voltage between a tip and a substrate.

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

    SciTech Connect

    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.

    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.

  6. KP-1212/1461, a nucleoside designed for the treatment of HIV by viral mutagenesis.

    PubMed

    Harris, Kevin S; Brabant, William; Styrchak, Sheila; Gall, Alexander; Daifuku, Richard

    2005-07-01

    We report the activities of a novel nucleoside analog against HIV. This nucleoside (KP-1212) is not a chain terminator but exerts its antiviral effects via mutagenesis of the viral genome. Serial passaging of HIV in the presence of KP-1212 causes an increase in the mutation rate of the virus leading to viral ablation. HIV strains resistant to KP-1212 have not yet been isolated. Quite to the contrary, virus treated with KP-1212 exhibited an increased sensitivity not only to KP-1212 but also to another nucleoside reverse transcriptase inhibitor (NRTI), zidovudine. HIV strains resistant to other NRTIs (e.g. zidovudine, lamivudine, stavudine, abacavir, etc.) exhibited no cross-resistance towards KP-1212. Multiple assays confirmed that KP-1212 has a favorable (low) genotoxicity profile when compared to some approved antiviral nucleosides. In addition, KP-1212 is not toxic to mitochondria nor does it exhibit any inhibitory effects on mitochondrial DNA synthesis. PMID:15890415

  7. The Role of Flexible Loops in Folding, Trafficking and Activity of Equilibrative Nucleoside Transporters

    PubMed Central

    Aseervatham, Jaya; Tran, Lucky; Machaca, Khaled; Boudker, Olga

    2015-01-01

    Equilibrative nucleoside transporters (ENTs) are integral membrane proteins, which reside in plasma membranes of all eukaryotic cells and mediate thermodynamically downhill transport of nucleosides. This process is essential for nucleoside recycling, and also plays a key role in terminating adenosine-mediated cellular signaling. Furthermore, ENTs mediate the uptake of many drugs, including anticancer and antiviral nucleoside analogues. The structure and mechanism, by which ENTs catalyze trans-membrane transport of their substrates, remain unknown. To identify the core of the transporter needed for stability, activity, and for its correct trafficking to the plasma membrane, we have expressed human ENT deletion mutants in Xenopus laevis oocytes and determined their localization, transport properties and susceptibility to inhibition. We found that the carboxyl terminal trans-membrane segments are essential for correct protein folding and trafficking. In contrast, the soluble extracellular and intracellular loops appear to be dispensable, and must be involved in the fine-tuning of transport regulation. PMID:26406980

  8. Comparison of nucleoside concentrations in blood of fish with and without tumors

    SciTech Connect

    Kuehl, D.W.; Johnson, R.D. ); Eisenschenk, L.; Naumann, S. ); Regal, R.; Barnidge, P. ); McKim, J. Jr. )

    1991-05-01

    The objective of this study was to develop and use HPLC based analytical methodology to characterize nucleosides in blood plasma and serum from fish with and without tumors, with a goal of determining if fish blood nucleoside concentrations could similarly be used as a bioindicator of tumor development in fish. The approach was to develop analytical methodology and quality assurance criteria for the analysis of nucleosides in fish blood, and to characterize nucleoside concentrations in blood of fish for which both healthy and tumor-bearing samples were available. Data would then be used to establish parameters with which tumor-bearing fish could be distinguished from healthy fish. Blood samples used to establish the diagnostic parameters were from control rainbow trout (Oncorhynchus mykiss) and those with tumors developed after exposure to aflatoxins. A second set of blood samples was from field collected black bullheads (Ictalurus melas).

  9. The Role of Flexible Loops in Folding, Trafficking and Activity of Equilibrative Nucleoside Transporters.

    PubMed

    Aseervatham, Jaya; Tran, Lucky; Machaca, Khaled; Boudker, Olga

    2015-01-01

    Equilibrative nucleoside transporters (ENTs) are integral membrane proteins, which reside in plasma membranes of all eukaryotic cells and mediate thermodynamically downhill transport of nucleosides. This process is essential for nucleoside recycling, and also plays a key role in terminating adenosine-mediated cellular signaling. Furthermore, ENTs mediate the uptake of many drugs, including anticancer and antiviral nucleoside analogues. The structure and mechanism, by which ENTs catalyze trans-membrane transport of their substrates, remain unknown. To identify the core of the transporter needed for stability, activity, and for its correct trafficking to the plasma membrane, we have expressed human ENT deletion mutants in Xenopus laevis oocytes and determined their localization, transport properties and susceptibility to inhibition. We found that the carboxyl terminal trans-membrane segments are essential for correct protein folding and trafficking. In contrast, the soluble extracellular and intracellular loops appear to be dispensable, and must be involved in the fine-tuning of transport regulation. PMID:26406980

  10. Lipophilic prodrugs of nucleoside triphosphates as biochemical probes and potential antivirals

    PubMed Central

    Gollnest, Tristan; de Oliveira, Thiago Dinis; Schols, Dominique; Balzarini, Jan; Meier, Chris

    2015-01-01

    The antiviral activity of nucleoside reverse transcriptase inhibitors is often limited by ineffective phosphorylation. We report on a nucleoside triphosphate (NTP) prodrug approach in which the γ-phosphate of NTPs is bioreversibly modified. A series of TriPPPro-compounds bearing two lipophilic masking units at the γ-phosphate and d4T as a nucleoside analogue are synthesized. Successful delivery of d4TTP is demonstrated in human CD4+ T-lymphocyte cell extracts by an enzyme-triggered mechanism with high selectivity. In antiviral assays, the compounds are potent inhibitors of HIV-1 and HIV-2 in CD4+ T-cell (CEM) cultures. Highly lipophilic acyl residues lead to higher membrane permeability that results in intracellular delivery of phosphorylated metabolites in thymidine kinase-deficient CEM/TK− cells with higher antiviral activity than the parent nucleoside. PMID:26503889

  11. a Nucleoside Under Observation in the Gas Phase: a Rotational Study of Uridine

    NASA Astrophysics Data System (ADS)

    Peña, Isabel; Alonso, José L.

    2014-06-01

    The nucleoside of uridine has been placed in the gas phase by laser ablation and the most stable C2{'}-anti conformation characterized by broadband chirped pulse (CP-FTMW) and narrowband molecular beam Fourier transform microwave (LA-MB-FTMW) spectroscopies. The quadrupole hyperfine structure, originated by two 14N nuclei, has been completely resolved. Intramolecular hydrogen bonds involving uracil and ribose moieties have been found to play an important role in the stabilization of the nucleoside.

  12. Enantioselective Intermolecular Cyclopropanations for the Synthesis of Chiral Pyrimidine Carbocyclic Nucleosides.

    PubMed

    Xie, Ming-Sheng; Zhou, Peng; Niu, Hong-Ying; Qu, Gui-Rong; Guo, Hai-Ming

    2016-09-01

    A direct route to chiral cyclopropylpyrimidine carbocyclic nucleoside analogues has been reported via highly enantioselective intermolecular cyclopropanation reactions of N1-vinylpyrimidines with α-diazoesters. With chiral ruthenium(II)-phenyloxazoline complex (2 mol %) as the catalyst, cyclopropyl pyrimidine nucleoside analogues could be obtained in good yields (71-96% yields) with high levels of diastereo- and enantioselectivities (10:1 to >20:1 dr and 96-99% ee) in 1 min. PMID:27526779

  13. Aberrant Apoptotic Response of Colorectal Cancer Cells to Novel Nucleoside Analogues

    PubMed Central

    Harmse, Leonie; Dahan-Farkas, Nurit; Panayides, Jenny-Lee; van Otterlo, Willem; Penny, Clement

    2015-01-01

    Despite the increased understanding of colorectal cancer and the introduction of targeted drug therapy, the metastatic phase of the disease remains refractory to treatment. Since the deregulation of normal apoptosis contributes to the pathogenesis of colorectal cancer, novel nucleoside analogues were synthesized here and evaluated for their ability to induce apoptosis and cause cell death in two colorectal adeno-carcinoma cell lines, Caco-2 and HT-29. Three novel nucleoside analogues assessed here showed cytotoxic activity, as measured by the MTT assay against both cell lines: the IC50 values ranged between 3 and 37 μM, with Caco-2 cells being more sensitive than HT-29 cells. Compared to camptothecin, the positive control, the nucleoside analogues were significantly less toxic to normal unstimulated leukocytes (p>0.05). Moreover, the nucleosides were able to induce apoptosis as measured by an increase in caspase 8 and caspase 3 activity above that of the control. This was additionally supported by data derived from Annexin V-FITC assays. Despite marginal changes to the mitochondrial membrane potential, all three nucleosides caused a significant increase in cytosolic cytochrome c (p>0.05), with a corresponding decrease in mitochondrial cytochrome c. Morphological analysis of both cell lines showed the rapid appearance of vacuoles following exposure to two of the nucleosides, while a third caused cellular detachment, delayed cytoplasmic vacuolisation and nuclear abnormalities. Preliminary investigations, using the autophagic indicator monodansylcadaverine and chloroquine as positive control, showed that two of the nucleosides induced the formation of autophagic vacuoles. In summary, the novel nucleoside analogues showed selective cytotoxicity towards both cancer cell lines and are effective initiators of an unusual apoptotic response, demonstrating their potential to serve as structural scaffolds for more potent analogues. PMID:26390405

  14. Mild, efficient, selective and "green" benzoylation of nucleosides using benzoyl cyanide in ionic liquid.

    PubMed

    Prasad, Ashok K; Kumar, Vineet; Maity, Jyotirmoy; Sanghvi, Yogesh S; Ravikumar, Vasulinga T; Parmar, Virinder S

    2005-01-01

    Use of benzoyl cyanide (BzCN) for benzoylation of nucleosides has been studied, both in pyridine and in ionic liquid BzCN in 1-methoxyethyl-3-methylimidazolium methanesulfonate as ionic liquid has been found to be a "green "alternative compared to the pyridine-BzCN system. An efficient and selective benzoylation of nucleosides of both, the 2'-deoxy- and the ribo-series at ambient temperature was accomplished. PMID:16248029

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

    PubMed

    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

  16. Recurrence of hyperprolactinemia and continuation of ovarian acyclicity in captive African elephants (Loxodonta africana) treated with cabergoline.

    PubMed

    Morfeld, Kari A; Ball, Ray L; Brown, Janine L

    2014-09-01

    Hyperprolactinemia is associated with reproductive acyclicity in zoo African elephants (Loxodonta africana) and may contribute to the non-self-sustainability of the captive population in North America. It is a common cause of infertility in women and other mammals and can be treated with the dopamine agonist cabergoline. The objectives of this study were to assess prolactin responses to cabergoline treatment in hyperprolactinemic, acyclic African elephants and to determine the subsequent impact on ovarian cyclic activity. Five elephants, diagnosed as hyperprolactinemic (>11 ng/ml prolactin) and acyclic (maintenance of baseline progestagens for at least 1 yr), were treated with 1-2 mg cabergoline orally twice weekly for 16-82 wk. Cabergoline reduced (P < 0.05) serum prolactin concentrations during the treatment period compared to pretreatment levels in four of five elephants (11.5 +/- 3.2 vs. 9.1 +/- 3.4 ng/ml; 20.3 +/- 16.7 vs. 7.9 +/- 9.8 ng/ml; 26.4 +/- 15.0 vs. 6.8 +/- 1.5 ng/ml; 42.2 +/- 22.6 vs. 18.6 +/- 8.9 ng/ml). However, none of the females resumed ovarian cyclicity based on serum progestagen analyses up to 1 yr posttreatment. In addition, within 1 to 6 wk after cessation of oral cabergoline, serum prolactin concentrations returned to concentrations that were as high as or higher than before treatment (P < 0.05). One elephant that exhibited the highest pretreatment prolactin concentration (75.2 +/- 10.5 ng/ml) did not respond to cabergoline and maintained elevated levels throughout the study. Thus, oral cabergoline administration reduced prolactin concentrations in elephants with hyperprolactinemia, but there was no resumption of ovarian cyclicity, and a significant prolactin rebound effect was observed. It is possible that higher doses or longer treatment intervals may be required for cabergoline treatment to result in permanent suppression of prolactin secretion and to mitigate associated ovarian cycle problems. PMID:25314824

  17. Complex regulation of nucleoside transporter expression in epithelial and immune system cells.

    PubMed

    Pastor-Anglada, M; Casado, F J; Valdés, R; Mata, J; García-Manteiga, J; Molina, M

    2001-01-01

    Nucleoside transporters have a variety of functions in the cell, such as the provision of substrates for nucleic acid synthesis and the modulation of purine receptors by determining agonist availability. They also transport a wide range of nucleoside-derived antiviral and anticancer drugs. Most mammalian cells co-express several nucleoside transporter isoforms at the plasma membrane, which are differentially regulated. This paper reviews studies on nucleoside transporter regulation, which has been extensively characterized in the laboratory in several model systems: the hepatocyte, an epithelial cell type, and immune system cells, in particular B cells, which are non-polarized and highly specialized. The hepatocyte co-expresses at least two Na+-dependent nucleoside transporters, CNT1 and CNT2, which are up-regulated during cell proliferation but may undergo selective loss in certain experimental models of hepatocarcinomas. This feature is consistent with evidence that CNT expression also depends on the differentiation status of the hepatocyte. Moreover, substrate availability also modulates CNT expression in epithelial cells, as reported for hepatocytes and jejunum epithelia from rats fed nucleotide-deprived diets. In human B cell lines, CNT and ENT transporters are co-expressed but differentially regulated after B cell activation triggered by cytokines or phorbol esters, as described for murine bone marrow macrophages induced either to activate or to proliferate. The complex regulation of the expression and activity of nucleoside transporters hints at their relevance in cell physiology. PMID:11396615

  18. Synthesis, DNA Polymerase Incorporation, and Enzymatic Phosphate Hydrolysis of Formamidopyrimidine Nucleoside Triphosphates

    PubMed Central

    Imoto, Shuhei; Patro, Jennifer N.; Jiang, Yu Lin; Oka, Natsuhisa; Greenberg, Marc M.

    2007-01-01

    The nucleoside triphosphates of N6-(2-deoxy-α,β-d-erythro-pentofuranosyl)-2,6-diamino-4-hydroxy-5-formamidopyrimidine (Fapy·dGTP) and its C-nucleoside analogue (β-C-Fapy·dGTP) were synthesized. The lability of the formamide group required that nucleoside triphosphate formation be carried out using an umpolung strategy in which pyrophosphate was activated toward nucleophilic attack. The Klenow fragment of DNA polymerase I from Escherichia coli accepted Fapy·dGTP and β-C-Fapy·dGTP as substrates much less efficiently than it did dGTP. Subsequent extension of a primer containing either modified nucleotide was less affected compared to when the native nucleotide is present at the 3′-terminus. The specificity constants are sufficiently large that nucleoside triphosphate incorporation could account for the level of Fapy·dG observed in cells if 1% of the dGTP pool is converted to Fapy·dGTP. Similarly, polymerase-mediated introduction of β-C-Fapy·dG could be useful for incorporating useful amounts of this nonhydrolyzable analogue for use as an inhibitor of base excision repair. The kinetic viability of these processes is enhanced by inefficient hydrolysis of Fapy·dGTP and β-C-Fapy·dGTP by MutT, the E. coli enzyme that releases pyrophosphate and the corresponding nucleoside monophosphate upon reaction with structurally related nucleoside triphosphates. PMID:17090045

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

    PubMed

    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

  20. Atomistic Simulations of Perfluoro Phosphonic and Phosphinic Acid Membranes and Comparisons to Nafion

    SciTech Connect

    Idupulapati, Nagesh B.; Devanathan, Ramaswami; Dupuis, Michel

    2011-03-31

    We used classical molecular dynamics (MD) simulations to investigate the nanoscale morphology and proton transport properties of perfluoro phosphonic (FPA) and phosphinic acid (FPA-I) membranes as they are being considered for use in low temperature fuel cells. We systematically investigated these properties as a function of the hydration level. The changes in nanostructure, in transport dynamics of water and hydronium ions, and in water network percolation were extracted from MD simulations and compared with Nafion. Phosphonic and phosphinic acid moieties in FPA and FPA-I, have lower acidity than sulfonic acid in Nafion, yet the diffusion of water was observed to be faster in FPA and FPA-I than in Nafion, particularly at low hydration levels. However this did not give rise to notable differences in hydronium ion diffusion and water network percolation for these membranes over Nafion. Similar observations were also reported by our group recently in a study of perfluoro-sulfonyl imide membranes carrying stronger super-acids than sulfonic acid of Nafion. These findings together suggest no strong apparent correlation between the acidity strength of the functional acid groups and the dynamics of water and hydronium ions in hydrated polymer electrolyte membranes (PEMs) with similar fluorocarbon backbones and acidic group-carrying side chains. This work was supported by the US Department of Energy Basic Energy Sciences' Chemical Sciences, Geosciences & Biosciences Division. Pacific Northwest National Laboratory is operated by Battelle for the US Department of Energy.

  1. Synthesis of polymeric phosphonates for selective delivery of radionuclides to osteosarcoma.

    PubMed

    Popwell, Sam J; Schulz, Michael D; Wagener, Kenneth B; Batich, Christopher D; Milner, Rowan J; Lagmay, Joanne; Bolch, Wesley E

    2014-09-01

    Discussed in detail is the synthesis and primary structure characterization of two polymers aimed at advancing the treatment of pediatric osteosarcoma. These polymers are designed to systemically deliver radiometals specifically to osteosarcomas using the passive targeting mechanism of enhanced permeability and retention (the EPR effect). The approach begins with the synthesis of a polymer capable of binding radiometals, for which prior data show improved site-specific targeting of solid tumors. Building on this success, a second polymer has been designed for improving the efficacy of currently available radionuclide therapies by incorporating the FDA-approved small-molecule ligand Quadramet directly onto the polymer structure. Time-activity curves of the phosphonate-functionalized polymers show rapid clearance from the central compartment and nontargeted organs, with up to 65% of injected activity being excreted within 3 hours. Both polymer ligands demonstrate good osteosarcoma targeting capability with little to no uptake in organs associated with the dose-limiting bone marrow. Additionally, biodistribution studies in nonosseous tumor models demonstrate the tumor targeting mechanism of the polymer ligands, which appears to be influenced by the high affinity of the phosphonate functionality for the positively charged hydroxyapatite mineral found in bone tumors. PMID:25111903

  2. Efficient functionalization of magnetite nanoparticles with phosphonate using a one-step continuous hydrothermal process.

    PubMed

    Thomas, Guillaume; Demoisson, Frédéric; Boudon, Julien; Millot, Nadine

    2016-06-28

    For the first time, phosphonate-functionalized magnetite nanoparticles (Fe3O4 NPs) were synthesized using a one-step continuous hydrothermal process. The NP surface was modified using a hydrophilic organic molecule, namely 6-phosphonohexanoic acid (PHA). NPs were fully characterized (TEM, XRD, DLS, ζ-potential, TGA, FTIR, XPS and specific surface area measurements) in order to investigate PHA effect on size, oxidation state, anchoring and colloidal stability. PHA reduced the crystallite size and size distribution and improved greatly colloidal stability when compared with bare Fe3O4 NPs. Moreover, PHA was grafted on the NP surface according to three different conformations: as mononuclear monodendates, as binuclear bidentates or as lying-down complexes. This report is very promising regarding the stabilization and functionalization of Fe3O4 NPs by phosphonate molecules under continuous hydrothermal conditions. The post-grafting of polymers such as polyethylene glycol can be considered owing to the presence of free carboxyl groups (-COOH) on the surface of Fe3O4 NPs. PMID:27295502

  3. Exciton-blocking phosphonic acid-treated anode buffer layers for organic photovoltaics

    NASA Astrophysics Data System (ADS)

    Zimmerman, Jeramy D.; Song, Byeongseop; Griffith, Olga; Forrest, Stephen R.

    2013-12-01

    We demonstrate significant improvements in power conversion efficiency of bilayer organic photovoltaics by replacing the exciton-quenching MoO3 anode buffer layer with an exciton-blocking benzylphosphonic acid (BPA)-treated MoO3 or NiO layer. We show that the phosphonic acid treatment creates buffers that block up to 70% of excitons without sacrificing the hole extraction efficiency. Compared to untreated MoO3 anode buffers, BPA-treated NiO buffers exhibit a ˜ 25% increase in the near-infrared spectral response in diphenylanilo functionalized squaraine (DPSQ)/C60-based bilayer devices, increasing the power conversion efficiency under 1 sun AM1.5G simulated solar illumination from 4.8 ± 0.2% to 5.4 ± 0.3%. The efficiency can be further increased to 5.9 ± 0.3% by incorporating a highly conductive exciton blocking bathophenanthroline (BPhen):C60 cathode buffer. We find similar increases in efficiency in two other small-molecule photovoltaic systems, indicating the generality of the phosphonic acid-treated buffer approach to enhance exciton blocking.

  4. Thermodynamics and Phase Behavior of Phosphonated Block Copolymers Containing Ionic Liquids

    NASA Astrophysics Data System (ADS)

    Jung, Ha Young; Park, Moon Jeong

    Charge-containing copolymers have drawn intensive attention in recent years for their uses in wide range of electrochemical devices such as fuel cells, lithium batteries and actuators. Particularly, the creation of microphase-separated morphologies in such materials by designing them in block and graft configurations has been the subject of extensive studies, in order to establish a synergistic means of optimizing ion transport properties and mechanical integrity. Interest in this topic has been further stimulated by intriguing phase behavior from charge-containing polymers, which was not projected from conventional phase diagrams of non-ionic polymers. Herein, we investigate thermodynamics and phase behavior of a set of phosphonated block copolymers. By synthesizing low-molecular weight samples with degree of polymerization (N) <35, we observed order-disorder transition that enabled us to estimate effective Flory-Huggins interaction parameters (χ) by using random phase approximation. We further examined the systems by adding various ionic liquids, where noticeable increases in χ values and modulated microphase separation behavior were observed. The morphology-conductivity relationship has been elucidated by taking into account the segmental motion of polymer chains, volume of conducting phases, and the molecular interactions between phosphonated polymer chains and cations of ionic liquids.

  5. Phosphonic pseudopeptides as human neutrophil elastase inhibitors--a combinatorial approach.

    PubMed

    Sieńczyk, Marcin; Podgórski, Dawid; Błażejewska, Aleksandra; Kulbacka, Julita; Saczko, Jolanta; Oleksyszyn, Józef

    2011-02-01

    Here we present a simple and rapid method for the construction of phosphonic peptide mimetic inhibitor libraries-products of Ugi and Passerini multicomponent condensations-leading to the selection of new biologically active phosphonic pseudopeptides. As the starting isonitriles, 1-isocyanoalkylphosphonate diaryl ester derivatives were applied. The structure of the synthesized inhibitors was designed to target human neutrophil elastase, a serine protease whose uncontrolled activity may lead to development of several pathophysiological states such as rheumatoid arthritis, cystic fibrosis or tumor growth and invasion. After screening the inhibitory activity of our constructed libraries, the most active compounds were synthesized as single molecules. One of the obtained inhibitors, Cbz-Met-O-Met-Val(P)(OC(6)H(4)-p-Cl)(2), displayed apparent second-order inhibition value at 40,105M(-1)s(-1) as the diastereomers mixture. Inhibition potency and selectivity of action toward other serine proteases as well as the results of initial in vitro experiments regarding inhibitors influence on cancer cell proliferation are presented. PMID:21216608

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

    PubMed Central

    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

  7. An ATR-FTIR study of different phosphonic acids in aqueous solution.

    PubMed

    Zenobi, María C; Luengo, Carina V; Avena, Marcelo J; Rueda, Elsa H

    2008-07-01

    An ATR-FIR study of the vibrational spectra of 1-hydroxyethane-1,1'-diphosphonic acid (HEDP), nitrilotris(methylenephosphonic acid) (NTMP) and N,N-bis(2-hydroxyethyl)aminomethylphosphonic acid (BHAMP) in aqueous solution is presented. The study was performed in the range of pH from 5 to 9, and bands assignments are given in the 2000-890 cm(-1) range. However, as phosphonates display bands due to the PO stretching vibration mainly in the 900-1200 cm(-1) range, the study is focused in this midinfrared region, which shows important changes as the pH changes, specially the nu(POH) at approximately 925 cm(-1) and nu(PO(3)(2-)) at approximately 970 cm(-1) vibrations. IR analyses give also evidences for the zwitterionic nature of BHAMP and NTMP in solution with a strong indication that the zwitterion in both compounds remains intact throughout the pH range investigated. The successive protonation steps with the decrease of pH were evidenced in the IR spectra of the three studied phosphonates. PMID:17826311

  8. An ATR-FTIR study of different phosphonic acids in aqueous solution

    NASA Astrophysics Data System (ADS)

    Zenobi, María C.; Luengo, Carina V.; Avena, Marcelo J.; Rueda, Elsa H.

    2008-07-01

    An ATR-FIR study of the vibrational spectra of 1-hydroxyethane-1,1'-diphosphonic acid (HEDP), nitrilotris(methylenephosphonic acid) (NTMP) and N, N-bis(2-hydroxyethyl)aminomethylphosphonic acid (BHAMP) in aqueous solution is presented. The study was performed in the range of pH from 5 to 9, and bands assignments are given in the 2000-890 cm -1 range. However, as phosphonates display bands due to the P sbnd O stretching vibration mainly in the 900-1200 cm -1 range, the study is focused in this midinfrared region, which shows important changes as the pH changes, specially the ν(P sbnd OH) at ˜925 cm -1 and ν(PO 32-) at ˜970 cm -1 vibrations. IR analyses give also evidences for the zwitterionic nature of BHAMP and NTMP in solution with a strong indication that the zwitterion in both compounds remains intact throughout the pH range investigated. The successive protonation steps with the decrease of pH were evidenced in the IR spectra of the three studied phosphonates.

  9. Use of bifunctional phosphonates for the preparation of heterobimetallic 5f-3d systems.

    PubMed

    Alsobrook, Andrea N; Zhan, Wei; Albrecht-Schmitt, Thomas E

    2008-06-16

    The hydrothermal reaction of phosphonoacetic acid (H2PO3CH2C(O)OH, PAA) with UO3 and Cu(C2H3O2)2 .H2O results in the formation of the crystalline heterobimetallic uranium(VI)/copper(II) phosphonates UO2Cu(PO3CH2CO2)(OH)(H2O)2 ( UCuPAA-1), (UO2) 2Cu(PO3CH2CO2)2(H2O)3 (UCuPAA-2), and [H3O][(UO2) 2Cu2(PO3CH2CO2)3(H2O)2 ( UCuPAA-3). The addition of sodium hydroxide to the aforementioned reactions results in the formation of Na[UO2(PO3CH2CO2)].2H2O (NaUPAA-1). These compounds display 1D (UCuPAA-1), 2D (UCuPAA-2, NaUPAA-1), and 3D (UCuPAA-3) architectures wherein the phosphonate portion of the ligand primarily coordinates the uranium(VI) centers; whereas the carboxylate moiety preferentially, but not exclusively, binds to the copper(II) ions. Fluorescence measurements on all four compounds demonstrate that the presence of copper(II) mostly quenches the emission from the uranyl moieties. PMID:18494466

  10. Thermal stability and ordering study of long- and short-alkyl chain phosphonic acid multilayers.

    PubMed

    de Pauli, Muriel; Prado, Mariana de Castro; Matos, Matheus Josue Souza; Fontes, Giselle Nogueira; Perez, Carlos Alberto; Mazzoni, Mario Sergio Carvalho; Neves, Bernardo Ruegger Almeida; Malachias, Angelo

    2012-10-30

    Long-range order evolution of self-assembled phosphonic acid multilayers as a function of temperature is studied here for two molecules with different alkyl chain length. By using synchrotron conventional diffraction, distinct order configurations are retrieved on phosphonic acid multilayers and their thermodynamic behavior monitored by energy-dispersive diffraction. This later technique allows us to observe the system behavior near order-disorder temperatures, as well as to determine the most stable configurations in the range from room temperature up to 120 °C. Planar order is also addressed by wide-angle X-ray scattering (WAXS) transmission experiments. Order parameter phase diagrams are built based on the experimental results, showing the dominant configuration at each temperature. The multilayer molecular long-range order retrieved from the experiments is corroborated by first principles calculations based on the Density Functional Theory. The bulk configurations depicted in this work are produced by molecule-molecule interactions and allow for future comparisons with the behavior of ordered molecules in few-monolayers configurations, commonly used in organic devices, where the presence of surfaces and interfaces strongly affects the molecule packing. PMID:23009090

  11. Conserved biosynthetic pathways for phosalacine, bialaphos and newly discovered phosphonic acid natural products.

    PubMed

    Blodgett, Joshua A V; Zhang, Jun Kai; Yu, Xiaomin; Metcalf, William W

    2016-01-01

    Natural products containing phosphonic or phosphinic acid functionalities often display potent biological activities with applications in medicine and agriculture. The herbicide phosphinothricin-tripeptide (PTT) was the first phosphinate natural product discovered, yet despite numerous studies, questions remain surrounding key transformations required for its biosynthesis. In particular, the enzymology required to convert phosphonoformate to carboxyphosphonoenolpyruvate and the mechanisms underlying phosphorus methylation remain poorly understood. In addition, the model for non-ribosomal peptide synthetase assembly of the intact tripeptide product has undergone numerous revisions that have yet to be experimentally tested. To further investigate the biosynthesis of this unusual natural product, we completely sequenced the PTT biosynthetic locus from Streptomyces hygroscopicus and compared it with the orthologous cluster from Streptomyces viridochromogenes. We also sequenced and analyzed the closely related phosalacine (PAL) biosynthetic locus from Kitasatospora phosalacinea. Using data drawn from the comparative analysis of the PTT and PAL pathways, we also evaluate three related recently discovered phosphonate biosynthetic loci from Streptomyces sviceus, Streptomyces sp. WM6386 and Frankia alni. Our observations address long-standing biosynthetic questions related to PTT and PAL production and suggest that additional members of this pharmacologically important class await discovery. PMID:26328935

  12. Conserved biosynthetic pathways for phosalacine, bialaphos and newly discovered phosphonic acid natural products

    PubMed Central

    Blodgett, Joshua A. V; Zhang, Jun Kai; Yu, Xiaomin; Metcalf, William W.

    2015-01-01

    Natural products containing phosphonic or phosphinic acid functionalities often display potent biological activities with applications in medicine and agriculture. The herbicide phosphinothricin-tripeptide (PTT) was the first phosphinate natural product discovered, yet despite numerous studies, questions remain surrounding key transformations required for its biosynthesis. In particular, the enzymology required to convert phosphonoformate to carboxyphosphonoenolpyruvate and the mechanisms underlying phosphorus-methylation remain poorly understood. In addition, the model for NRPS assembly of the intact tripeptide product has undergone numerous revisions that have yet to be experimentally tested. To further investigate the biosynthesis of this unusual natural product, we completely sequenced the PTT biosynthetic locus from Streptomyces hygroscopicus and compared it to the orthologous cluster from Streptomyces viridochromogenes. We also sequenced and analysed the closely related phosalacine (PAL) biosynthetic locus from Kitasatospora phosalacinea. Using data drawn from the comparative analysis of the PTT and PAL pathways, we also evaluate three related recently discovered phosphonate biosynthetic loci from Streptomyces sviceus, Streptomyces sp. WM6386 and Frankia alni. Our observations address long-standing biosynthetic questions related to PTT and PAL production and suggest that additional members of this pharmacologically important class await discovery. PMID:26328935

  13. Phosphonate Analogs of 2-Oxoglutarate Perturb Metabolism and Gene Expression in Illuminated Arabidopsis Leaves

    PubMed Central

    Araújo, Wagner L.; Tohge, Takayuki; Nunes-Nesi, Adriano; Daloso, Danilo M.; Nimick, Mhairi; Krahnert, Ina; Bunik, Victoria I.; Moorhead, Greg B. G.; Fernie, Alisdair R.

    2012-01-01

    Although the role of the 2-oxoglutarate dehydrogenase complex (2-OGDHC) has previously been demonstrated in plant heterotrophic tissues its role in photosynthetically active tissues remains poorly understood. By using a combination of metabolite and transcript profiles we here investigated the function of 2-OGDHC in leaves of Arabidopsis thaliana via use of specific phosphonate inhibitors of the enzyme. Incubation of leaf disks with the inhibitors revealed that they produced the anticipated effects on the in situ enzyme activity. In vitro experiments revealed that succinyl phosphonate (SP) and a carboxy ethyl ester of SP are slow-binding inhibitors of the 2-OGDHC. Our results indicate that the reduced respiration rates are associated with changes in the regulation of metabolic and signaling pathways leading to an imbalance in carbon-nitrogen metabolism and cell homeostasis. The inducible alteration of primary metabolism was associated with altered expression of genes belonging to networks of amino acids, plant respiration, and sugar metabolism. In addition, by using isothermal titration calorimetry we excluded the possibility that the changes in gene expression resulted from an effect on 2-oxoglutarate (2OG) binding to the carbon/ATP sensing protein PII. We also demonstrated that the 2OG degradation by the 2-oxoglutarate dehydrogenase strongly influences the distribution of intermediates of the tricarboxylic acid (TCA) cycle and the GABA shunt. Our results indicate that the TCA cycle activity is clearly working in a non-cyclic manner upon 2-OGDHC inhibition during the light period. PMID:22876250

  14. Redox reaction between amino-(3,4-dihydroxyphenyl)methyl phosphonic acid and dopaquinone is responsible for the apparent inhibitory effect on tyrosinase.

    PubMed

    Gasowska, Beata; Wojtasek, Hubert; Hurek, Józef; Drag, Marcin; Nowak, Kornel; Kafarski, Paweł

    2002-08-01

    Amino-(3,4-dihydroxyphenyl)methyl phosphonic acid, the phosphonic analog of 3,4-dihydroxyphenylglycine, had been previously reported as a potent inhibitor of tyrosinase. The mechanism of the apparent enzyme inhibition by this compound has now been established. Amino-(3,4-dihydroxyphenyl)methyl phosphonic acid turned out to be a substrate and was oxidized to o-quinone, which evolved to a final product identified as 3,4-dihydroxybenzaldehyde, the same as for 3,4-dihydroxyphenylglycine. Monohydroxylated compounds (amino-(3-hydroxyphenyl)methyl phosphonic acid and amino-(4-hydroxyphenyl)methyl phosphonic acid) were not oxidized, neither was 4-hydroxy-l-phenylglycine. However, the relatively high Km for amino-(3,4-dihydroxyphenyl)methyl phosphonic acid (0.52 mm) indicated that competitive inhibition could not entirely explain the previously reported strong inhibitory effect (Ki = 50 and 97 micro m for tyrosine and 3-(3,4-dihydroxyphenyl)alanine (Dopa) as substrates, respectively). Neither was the enzyme covalently inactivated to a significant degree. Spectroscopic and electrochemical analysis of the oxidation of a mixture of Dopa and the inhibitor demonstrated that the phosphonic compound reduced dopaquinone back to Dopa, thus diminishing and delaying the formation of dopachrome. This produces an apparent strong inhibitory effect when the reaction is monitored spectrophotometrically at 475 nm. In this peculiar case Dopa acts as a redox shuttle mediating the oxidation of the shorter phosphonic homolog. Decomposition of the phosphonic o-quinone to 3,4-dihydroxybenzaldehyde drives the reaction against the slightly unfavorable difference in redox potentials. PMID:12180986

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

    PubMed

    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

  16. On the strong difference in reactivity of acyclic and cyclic diazodiketones with thioketones: experimental results and quantum-chemical interpretation

    PubMed Central

    Mereshchenko, Andrey S; Ivanov, Alexey V; Baranovskii, Viktor I; Rodina, Ludmila L

    2015-01-01

    Summary The 1,3-dipolar cycloaddition of acyclic 2-diazo-1,3-dicarbonyl compounds (DDC) and thioketones preferably occurs with Z,E-conformers and leads to the formation of transient thiocarbonyl ylides in two stages. The thermodynamically favorable further transformation of C=S ylides bearing at least one acyl group is identified as the 1,5-electrocyclization into 1,3-oxathioles. However, in the case of diazomalonates, the dominating process is 1,3-cyclization into thiiranes followed by their spontaneous desulfurization yielding the corresponding alkenes. Finally, carbocyclic diazodiketones are much less reactive under similar conditions due to the locked cyclic structure and are unfavorable for the 1,3-dipolar cycloaddition due to the Z,Z-conformation of the diazo molecule. This structure results in high, positive values of the Gibbs free energy change for the first stage of the cycloaddition process. PMID:25977725

  17. Kinetics and mechanism of the acid-catalyzed hydrolysis of a hypermodified nucleoside wyosine and its 5'-monophosphate.

    PubMed Central

    Golankiewicz, B; Zielonacka-Lis, E; Folkman, W

    1985-01-01

    The rates of acid-catalyzed hydrolysis of a hypermodified nucleoside, wyosine and its 5'-monophosphate were determined at various pH, temperature and buffer concentrations. The results show that despite distinct differences in structure and the glycosyl bond stability, the hydrolysis of wyosine proceeds via cleavage of the C-N bond by A-1 mechanism, analogously to simple nucleosides. Unlike majority of other monophosphates studied so far, wyosine 5'-monophosphate is not more stable than respective nucleoside. PMID:4000960

  18. Triple nucleoside reverse transcriptase inhibitor therapy in children.

    PubMed

    Handforth, Jennifer; Sharland, Mike

    2004-01-01

    Much of the success attributed to HIV therapy in the last few years has resulted from improved ways of using existing drugs in combination therapy regimens. The availability of new, more potent drugs such as protease inhibitors and more accurate viral load tests to aid decisions to start or change treatment has also contributed to the success. Published recommendations for pediatric HIV therapy, generated by a panel of experts and specialists, are readily available and regularly updated. Preferred regimens of 'potent' therapy (referred to as highly active antiretroviral therapy, or HAART) currently consist of two nucleoside reverse transcriptase inhibitors (NRTIs) combined with either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor. More intense four-drug regimens using an NNRTI or a second protease inhibitor as a fourth drug are being evaluated. Problems with HAART include: unpalatable drug formulations and adverse effects, coupled with lack of data on the pharmacokinetics, efficacy, and safety of various drug combinations. Adherence is a major factor influencing the efficacy and outcome of antiretroviral therapy. Many children cannot adhere to complex multidrug regimens, which cause virologic failure, despite excellent CD4+ cell count responses. This means a rapid progression through the limited number of treatment regimens available. Simpler regimens such as those containing three NRTIs have been proposed as a method of treatment that will allow suppression of the virus, yet circumvent many of the problems previously mentioned. An additional benefit would be the preservation of antiretroviral drugs from other classes for future treatment options if required. The major advantages of triple NRTI regimens are the simplicity of the regimen, good tolerability, few drug-drug interactions, and infrequent adverse effects coupled with a low pill burden. However, abacavir hypersensitivity remains a major problem. Up to 3% of patients may

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

    PubMed

    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

  20. A new chiral uranyl phosphonate framework consisting of achiral building units generated from ionothermal reaction: structure and spectroscopy characterizations.

    PubMed

    Zheng, Tao; Gao, Yang; Chen, Lanhua; Liu, Zhiyong; Diwu, Juan; Chai, Zhifang; Albrecht-Schmitt, Thomas E; Wang, Shuao

    2015-11-01

    The ionothermal reactions of uranyl nitrate and 1,3-pbpH4 (1,3-pbpH4 = 1,3-phenylenebis(phosphonic acid) ligand in ionic liquids of [C4mim][Dbp], [C4mpyr][Br], and [Etpy][Br], respectively, afforded three new uranyl phosphonates, namely [C4mim][(UO2)2(1,3-pbpH)(1,3-pbpH)·Hmim] (1), [UO2(1,3-pbpH2)H2O·mpr] (2), and [Etpy][UO2(1,3-pbpH2)F] (3). Compound 1 exhibits a rare example of a chiral uranyl phosphonate 3D framework structure built from achiral building units of tetragonal bipyramidal uranium polyhedra and 1,3-pbp ligands. The structure adopts a network with channels extending along the b axis, which are filled with C4mim(+) and protonated 1-methylimidazole. In sharp contrast, compounds 2 & 3 both show pillared topology composed of uranyl pentagonal bipyramid polyhedra and phosphonate ligands. The layers are neutral in compound 2 with N-methylpyrrole molecules in the interlayer space, while compound 3 adopts anionic layer, and the charge is compensated with N-ethyl-pyridinium cations between the layers. Although compounds 1, 2, and 3 were synthesized under identical conditions with sole variation of the ionic liquid species, the resulting structures show a rich diversity in the local coordination environment of uranyl ions, the protonation of the phosphonate ligand, the conformation of ionic liquid ions, and the overall arrangement of the structure. All compounds were characterized by absorption, temperature dependent fluorescence, as well as infrared and Raman spectroscopies. PMID:26419426

  1. Nucleoside transporter subtype expression: effects on potency of adenosine kinase inhibitors

    PubMed Central

    Sinclair, C J D; Powell, A E; Xiong, W; LaRivière, C G; Baldwin, S A; Cass, C E; Young, J D; Parkinson, F E

    2001-01-01

    Adenosine kinase (AK) inhibitors can enhance adenosine levels and potentiate adenosine receptor activation. As the AK inhibitors 5′ iodotubercidin (ITU) and 5-amino-5′-deoxyadenosine (NH2dAdo) are nucleoside analogues, we hypothesized that nucleoside transporter subtype expression can affect the potency of these inhibitors in intact cells.Three nucleoside transporter subtypes that mediate adenosine permeation of rat cells have been characterized and cloned: equilibrative transporters rENT1 and rENT2 and concentrative transporter rCNT2. We stably transfected rat C6 glioma cells, which express rENT2 nucleoside transporters, with rENT1 (rENT1-C6 cells) or rCNT2 (rCNT2-C6 cells) nucleoside transporters.We tested the effects of ITU and NH2dAdo on [3H]-adenosine uptake and conversion to [3H]-adenine nucleotides in the three cell types. NH2dAdo did not show any cell type selectivity. In contrast, ITU showed significant inhibition of [3H]-adenosine uptake and [3H]-adenine nucleotide formation at concentrations ⩽100 nM in rENT1-C6 cells, while concentrations ⩾3 μM were required for C6 or rCNT2-C6 cells.Nitrobenzylthioinosine (NBMPR; 100 nM), a selective inhibitor of rENT1, abolished the effects of nanomolar concentrations of ITU in rENT1-C6 cells.This study demonstrates that the effects of ITU, but not NH2dAdo, in whole cell assays are dependent upon nucleoside transporter subtype expression. Thus, cellular and tissue differences in expression of nucleoside transporter subtypes may affect the pharmacological actions of some AK inhibitors. PMID:11682452

  2. Solution conformations of nucleoside analogues exhibiting antiviral activity against human immunodeficiency virus

    NASA Astrophysics Data System (ADS)

    Dijkstra, Sandra; Benevides, James M.; Thomas, George J.

    1991-01-01

    The molecular-conformational basis for HIV-1 antiviral activity of dideoxynucleoside analogues is unknown. A recent proposal by van Roey [1] that furanose sugar puckering in the C2' -endo family (namely C3' -exo) may account for the enhanced anti-HIV-1 activity of azidothymidine (AZT), dideoxythymidine (ddT) and dideoxycytidine (ddC) has been tested by conformational analysis of these and related agents, using laser Raman spectroscopy of their solutions and crystal structures. The results show that nucleoside analogues exhibiting anti-HIV-1 activity, including AZT, ddT and ddC, exist in solution with C3' -endo as the predominating sugar pucker. The C3' -endo solution conformations differ fundamentally from the C3' -exo conformations observed in the corresponding crystal structures. Accordingly, the crystal conformation cannot be responsible for enhanced recognition of these agents, either by nucleoside kinase or reverse transcriptase, as a mechanism to explain antiviral activity. The present findings suggest that C3' -endo sugear pucker, rather than C3' -exo pucker, or other puckers of the C2' -endo family, is more probably the required conformation for antivaral activity. The present work also shows that nucleoside phosphorylation does not, in general, change the preferred solution conformation of a nucleoside. Therefore, C3' -endo sugar pucker is likely to be the preferred conformation for both nucleoside kinase and reverse transcriptase recognition. In this study, the list of thymidine nucleoside conformation markers available from Raman spectra is extended and additional group frequency assignments for C3' -azido, C3' -deoxy and related nucleoside derivatives are provided.

  3. A Computational Study of Expanded Heterocyclic Nucleosides in DNA

    PubMed Central

    O'Daniel, Peter I.; Jefferson, Malcolm; Wiest, Olaf; Seley-Radtke, Katherine L.

    2008-01-01

    The first molecular dynamics study of a series of heterospacer-expanded tricyclic bases in DNA using modified force field parameters in AMBER is detailed. The expanded purine nucleoside monomers have been designed to probe the effects of a heteroaromatic spacer ring on the structure, function, and dynamics of the DNA helix. The heterobase scaffold has been expanded with a furan, pyrrole, or thiophene spacer ring. This structural modification increases the polarizability of the bases and provides an additional hydrogen bond donor with the amine hydrogen of the pyrrole ring or hydrogen bond acceptor with the furan or thiophene ring free electron pairs. The polarizability of the expanded bases were determined by AM1 calculations and the results of the MD simulations of 20-mers predict that the modified curvature of the expanded base leads to a much larger major groove, while the effect on the minor groove is negligible. Overall, the structure resembles A-DNA. MD simulations of 10-mers suggest that the balance between base pairing vs. base stacking and intercalation can be shifted towards the latter due to the increased surface area and polariz-ability of the expanded bases. PMID:18808194

  4. Interaction of purine bases and nucleosides with serum albumin

    NASA Astrophysics Data System (ADS)

    Sułkowska, A.; Michnik, A.

    1997-06-01

    The proton NMR spectra of alkyl derivatives of adenine and adenosine have been studied. High-resolution (400 MHz) proton spectra were recorded at 300 K at increasing concentrations of serum albumin. The dependence of the chemical shifts and the line width of the individual spectral lines on the protein concentration provides some detailed information about the nature of the complexes between the purine derivatives and albumin. Comparison of data for the methylated and non-methylated purine bases and nucleosides indicates the formation of non-specific complexes with serum albumin. However, the presence of the ethyl group in 8-ethyl-9 N-methyladenine means that in the adenine derivative-serum albumin complex the ethyl chain preserves its dominant role in binding. An advantage of our model is that the π-π interaction between the adenine ring and the amino acids of the protein can be replaced by hydrophobic interaction in the case of complexation of the ethyl adenine derivative.

  5. DNA nucleoside composition and methylation in several species of microalgae

    SciTech Connect

    Jarvis, E.E.; Dunahay, T.G.; Brown, L.M. )

    1992-06-01

    Total DNA was isolated from 10 species of microalgae, including representatives of the Chlorophyceae (Chlorella ellipsoidea, Chlamydomonas reinhardtii, and Monoraphidium minutum), Bacillariophyceae (Cyclotella cryptica, Navicula saprophila, Nitzschia pusilla, and Phaeodactylum tricornutum), Charophyceae (Stichococcus sp.), Dinophyceae (Crypthecodinium cohnii), and Prasinophyceae (Tetraselmis suecica). Control samples of Escherichia coli and calf thymus DNA were also analyzed. The nucleoside base composition of each DNA sample was determined by reversed-phase high performance liquid chromatography. All samples contained 5-methyldeoxycytidine, although at widely varying levels. In M. minutum, about one-third of the cytidine residues were methylated. Restriction analysis supported this high degree of methylation in M. minutum and suggested that methylation is biased toward 5[prime]-CG dinucleotides. The guanosine + cytosine (GC) contents of the green algae were, with the exception of Stichococcus sp., consistently higher than those of the diatoms. Monoraphidium minutum exhibited an extremely high GC content of 71%. Such a value is rare among eukaryotic organisms and might indicate an unusual codon usage. This work is important for developing strategies for transformation and gene cloning in these algae. 46 refs., 1 fig., 2 tabs.

  6. Fluorescent pyrimidopyrimidoindole nucleosides: control of photophysical characterizations by substituent effects.

    PubMed

    Mizuta, Masahiro; Seio, Kohji; Miyata, Kenichi; Sekine, Mitsuo

    2007-07-01

    10-(2-Deoxy-beta-D-ribofuranosyl)pyrimido[4',5':4,5]pyrimido[1,6-a]indole-6,9(7H)-dione (dCPPI) and its derivatives were synthesized via the Suzuki-Miyaura coupling reaction of 5-iododeoxycytidine with 5-substituted N-Boc-indole-2-borates and characterized by UV-vis and fluorescence spectroscopy. The new fluorescent nucleosides showed rather large Stokes shifts (116-139 nm) in an aqueous buffer. The fluorescent intensities were dependent on the nature of the substituents on the indole rings. The electron-withdrawing groups increased the fluorescent intensity while the electron-donating groups having lone pairs decreased it. Among the substituted dCPPI derivatives tested, the trimethylammonium derivative of dCPPI was found to emit the brightest fluorescent light. The solvatochromism of dCPPI and its derivatives was also studied. Some of the dCPPI derivatives showed interesting solvent-dependent fluorescence enhancement and could be useful as new fluorescent structural probes for nucleic acids. The Lippert-Mataga analyses of the Stokes shift were also carried out to obtain estimated values of the dipole moment of the excited states of some of the derivatives. PMID:17555352

  7. Tuning the molecular order of C60 functionalized phosphonic acid monolayers.

    PubMed

    Rumpel, Armin; Novak, Michael; Walter, Johannes; Braunschweig, Björn; Halik, Marcus; Peukert, Wolfgang

    2011-12-20

    Mixed self-assembled monolayers (SAM) of alkyl phosphonic acids and C(60) functionalized octadecyl phosphonic acids (C(60)C(18)-PA) are deposited on alumina substrates from solution and are shown to form well-ordered structures with an insulating layer of alkyl chains and a semiconducting layer that comprises mainly C(60). Such an ordered structure is a necessity for the application of SAMs in organic transistors but is difficult to obtain since C(60)C(18)-PA without additional support do self-assemble in dense packaging but not in a well-ordered fashion. To avoid disordering of the SAM and to gain a better control of the interfacial properties we have investigated the stabilizing effects of fluorinated dodecyl phosphonic acids (FC(12)-PA) on the C(60)C(18)-PA monolayer. Vibrational sum-frequency (SFG) spectroscopy, ellipsometry, X-ray photoelectron spectroscopy, and electrical measurements were applied to study the mixed monolayers. Here, we make use of the differently labeled PA to determine surface coverages and molecular properties of the two species independently. Adsorption of FC(12)-PA gives rise to vibrational bands at 1344 cm(-1) and 1376 cm(-1) in SFG spectra, while a pronounced vibrational band centered at 1465 cm(-1) is attributable to C(60) vibrations. The coexistence of the bands is indicative for the presence of a mixed monolayer that is composed of both molecular species. Furthermore, a pronounced maximum in SFG intensity of the C(60) band is observed for SAMs, which are deposited from solutions with ~75% C(60)C(18)-PA and ~25% FC(12)-PA. The intensity maximum originates from successful stabilization of C(60) modified C(60)C(18)-PA by FC(12)-PA and a significantly improved molecular order. Conclusions from SFG spectra are corroborated by electric measurements that show best performance at these concentrations. Our results provide new information on the morphology and composition of C(60) modified SAMs and establish a route to fabricate well

  8. Phosphonate analogues of carboxypeptidase A substrates are potent transition-state analogue inhibitors.

    PubMed

    Hanson, J E; Kaplan, A P; Bartlett, P A

    1989-07-25

    Analogues of tri- and tetrapeptide substrates of carboxypeptidase A in which the scissile peptide linkage is replaced with a phosphonate moiety (-PO2--O-) were synthesized and evaluated as inhibitors of the enzyme. The inhibitors terminated with either L-lactate or L-phenyllactate [designated (O) Ala and (O) Phe, respectively] in the P1' position. Transition-state analogy was shown for a series of 14 tri- and tetrapeptide derivatives containing the structure RCO-AlaP-(O)Ala [RCO-AP(O)A, AP indicates the phosphonic acid analogue of alanine] by the correlation of the Ki values for the inhibitors and the Km/kcat values for the corresponding amide substrates. This correlation supports a transition state for the enzymatic reaction that resembles the tetrahedral intermediate formed upon addition of water to the scissile carbonyl group. The inhibitors containing (O) Phe at the P1' position proved to be the most potent reversible inhibitors of carboxypeptidase A reported to date: the dissociation constants of ZAFP(O)F, ZAAP(O)F, and ZFAP(O)F are 4, 3, and 1 pM, respectively. Because of the high affinity of these inhibitors, their dissociation constants could not be determined by steady-state methods. Instead, the course of the association and dissociation processes was monitored for each inhibitor as its equilibrium with the enzyme was established in both the forward and reverse directions. A phosphonamidate analogue, ZAAPF, in which the peptide linkage is replaced with a -PO2-NH- moiety, was prepared and shown to hydrolyze rapidly at neutral pH (t1/2 = 20 min at pH 7.5). This inhibitor is bound an order of magnitude less tightly than the corresponding phosphonate, ZAAP(O)F, a result that contrasts with the 840-fold higher affinity of phosphonamidates for thermolysin [Bartlett, P. A., & Marlowe, C. K. (1987) Science 235, 569-571], a zinc peptidase with a similar arrangement of active-site catalytic residues. PMID:2790000

  9. Allelic isoforms of the H+/nucleoside co-transporter (CaCNT) from Candida albicans reveal separate high- and low-affinity transport systems for nucleosides.

    PubMed

    Slugoski, Melissa D; Loewen, Shaun K; Ng, Amy M L; Baldwin, Stephen A; Cass, Carol E; Young, James D

    2004-11-01

    Contigs 19-10196 and 19-20196 of the Stanford Candida albicans genome sequence databank encode two putative allelic isoforms of C. albicans CaCNT, a recently characterized 608 amino acid residue H+-coupled fungal member of the CNT family of concentrative nucleoside transport proteins. The single Ser/Gly difference between CaCNT/19-20196 and CaCNT occurs at position 328 in putative TM 7, and corresponds to a Ser/Gly substitution previously shown to contribute to the contrasting pyrimidine and purine nucleoside selectivities of human (h) and rat (r) Na+-dependent CNT1 and CNT2. CaCNT/19-10196 differs from CaCNT by four amino acids, but has Gly at position 328. These new proteins were recreated by site-directed mutagenesis of CaCNT and characterized functionally by heterologous expression in Xenopus laevis oocytes. In marked contrast to h/rCNT1/2, both CaCNT/19-10196 and CaCNT/19-20196 exhibited permeant selectivities for purine nucleosides (adenosine, guanosine and inosine) and uridine similar to that of CaCNT. However, although H+-coupled, CaCNT/19-20196 exhibited a approximately 10-fold higher apparent Km for uridine than either CaCNT or CaCNT/19-10196. CaCNT/19-20196 also exhibited a low apparent affinity for inosine. We conclude that the three proteins correspond to high-affinity (CaCNT, CaCNT/19-10196) and low-affinity (CaCNT/19-20196) allelic isoforms of the C. albicans CNT nucleoside transporter. This is the first example of a single amino acid residue substitution altering a CNT protein's overall apparent affinity for nucleosides. PMID:15543539

  10. Synthesis of purine and 7-deazapurine nucleoside analogues of 6-N-(4-Nitrobenzyl)adenosine; inhibition of nucleoside transport and proliferation of cancer cells.

    PubMed

    Rayala, Ramanjaneyulu; Theard, Patricia; Ortiz, Heysell; Yao, Sylvia; Young, James D; Balzarini, Jan; Robins, Morris J; Wnuk, Stanislaw F

    2014-09-01

    Human equilibrative nucleoside transporter 1 (hENT1) is a prototypical nucleoside transporter protein ubiquitously expressed on the cell surface of almost all human tissue. Given the role of hENT1 in the transport of nucleoside drugs, an important class of therapeutics in the treatment of various cancers and viral infections, efforts have been made to better understand the mechanisms by which hENT1 modulates nucleoside transport. To that end, we report here the design and synthesis of novel tool compounds for the further study of hENT1. The 7-deazapurine nucleoside antibiotic tubercidin was converted into its 4-N-benzyl and 4-N-(4-nitrobenzyl) derivatives by alkylation at N3 followed by a Dimroth rearrangement to the 4-N-isomer or by fluoro-diazotization followed by SN Ar displacement of the 4-fluoro group by a benzylamine. The 4-N-(4-nitrobenzyl) derivatives of sangivamycin and toyocamycin antibiotics were prepared by the alkylation approach. Cross-membrane transport of labeled uridine by hENT1 was inhibited to a weaker extent by the 4-nitrobenzylated tubercidin and sangivamycin analogues than was observed with 6-N-(4-nitrobenzyl)adenosine. Type-specific inhibition of cancer cell proliferation was observed at micromolar concentrations with the 4-N-(4-nitrobenzyl) derivatives of sangivamycin and toyocamycin, and also with 4-N-benzyltubercidin. Treatment of 2',3',5'-O-acetyladenosine with aryl isocyanates gave the 6-ureido derivatives but none of them exhibited inhibitory activity against cancer cell proliferation or hENT1. PMID:24788480

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

    PubMed

    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

  12. Saturable Hepatic Extraction of Gemcitabine Involves Biphasic Uptake Mediated by Nucleoside Transporters Equilibrative Nucleoside Transporter 1 and 2.

    PubMed

    Shimada, Takuya; Nakanishi, Takeo; Tajima, Hidehiro; Yamazaki, Maiko; Yokono, Rina; Takabayashi, Makiko; Shimada, Tsutomu; Sawamoto, Kazuki; Miyamoto, Ken-Ichi; Kitagawa, Hirohisa; Ohta, Tetsuo; Tamai, Ikumi; Sai, Yoshimichi

    2015-09-01

    Hepatic arterial infusion (HAI) chemotherapy with gemcitabine (GEM) is expected to be more effective and safer method to treat hepatic metastasis of pancreatic cancer compared with intravenous administration, because it affords higher tumor exposure with lower systemic exposure. Thus, a key issue for dose selection is the saturability of hepatic uptake of GEM. Therefore, we investigated GEM uptake in rat and human isolated hepatocytes. Hepatic GEM uptake involved high- and low-affinity saturable components with Km values of micromolar and millimolar order, respectively. The uptake was inhibited concentration dependently by S-(4-nitrobenzyl)-6-thioinosine (NBMPR) and was sodium-ion-independent, suggesting a contribution of equilibrative nucleoside transporters (ENTs). The concentration dependence of uptake in the presence of 0.1 μM NBMPR showed a single low-affinity binding site. Therefore, the high- and low-affinity sites correspond to ENT1 and ENT2, respectively. Our results indicate hepatic extraction of GEM is predominantly mediated by the low-affinity site (hENT2), and at clinically relevant hepatic concentrations of GEM, hENT2-mediated uptake would not be completely saturated. This is critical for HAI, because saturation of hepatic uptake would result in a marked increase of GEM concentration in the peripheral circulation, abrogating the advantage of HAI over intravenous administration in terms of severe adverse events. PMID:26037416

  13. Spectrum of activity and mechanisms of resistance of various nucleoside derivatives against gammaherpesviruses.

    PubMed

    Coen, Natacha; Duraffour, Sophie; Topalis, Dimitri; Snoeck, Robert; Andrei, Graciela

    2014-12-01

    The susceptibilities of gammaherpesviruses, including Epstein-Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus (KSHV), and animal rhadinoviruses, to various nucleoside analogs was investigated in this work. Besides examining the antiviral activities and modes of action of antivirals currently marketed for the treatment of alpha- and/or betaherpesvirus infections (including acyclovir, ganciclovir, penciclovir, foscarnet, and brivudin), we also investigated the structure-activity relationship of various 5-substituted uridine and cytidine molecules. The antiviral efficacy of nucleoside derivatives bearing substitutions at the 5 position was decreased if the bromovinyl was replaced by chlorovinyl. 1-β-D-Arabinofuranosyl-(E)-5-(2-bromovinyl)uracil (BVaraU), a nucleoside with an arabinose configuration of the sugar ring, exhibited no inhibitory effect against rhadinoviruses but was active against EBV. On the other hand, the fluoroarabinose cytidine analog 2'-fluoro-5-iodo-aracytosine (FIAC) showed high selectivity indices against gammaherpesviruses that were comparable to those of brivudin. Additionally, we selected brivudin- and acyclovir-resistant rhadinoviruses in vitro and characterized them by phenotypic and genotypic (i.e., sequencing of the viral thymidine kinase, protein kinase, and DNA polymerase) analysis. Here, we reveal key amino acids in these enzymes that play an important role in substrate recognition. Our data on drug susceptibility profiles of the different animal gammaherpesvirus mutants highlighted cross-resistance patterns and indicated that pyrimidine nucleoside derivatives are phosphorylated by the viral thymidine kinase and purine nucleosides are preferentially activated by the gammaherpesvirus protein kinase. PMID:25267682

  14. Cloning and functional expression of a complementary DNA encoding a mammalian nucleoside transport protein.

    PubMed

    Huang, Q Q; Yao, S Y; Ritzel, M W; Paterson, A R; Cass, C E; Young, J D

    1994-07-01

    Expression screening in Xenopus oocytes was used to isolate a cDNA from rat jejunal epithelium encoding a Na(+)-dependent nucleoside transport protein (named cNT1). The cDNA sequence of cNT1 predicts a protein of 648 amino acids (relative molecular mass 71,000) with 14 potential transmembrane domains. Data base searches indicate significant sequence similarity to the NUPC proton/nucleoside symporter of Escherichia coli. There is no sequence similarity between cNT1 and proteins of mammalian origin. Functionally, cNT1 exhibited the transport characteristics of the nucleoside transport system cit (selective for pyrimidine nucleosides and adenosine) and accepted both 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxycytidine (ddC) as permeants (Km = 0.49 and 0.51 mM, respectively). The demonstration of transport of AZT by cNT1 expressed in Xenopus oocytes provides the first direct evidence that AZT enters cells by transporter-mediated processes, as well as by passive diffusion. Consistent with the tissue distribution of system cit transport activity, transcripts for cNT1 were detected in kidney as well as jejunum. cNT1 therefore belongs to a potential new gene family and may be involved in the intestinal absorption and renal handling of pyrimidine nucleoside analogs used to treat acquired immunodeficiency syndrome (AIDS). PMID:8027026

  15. Supramolecular polymerization of a prebiotic nucleoside provides insights into the creation of sequence-controlled polymers

    DOE PAGESBeta

    Wang, Jun; Bonnesen, Peter V; Rangel, E.; Vallejo, E.; Sanchez-Castillo, Ariadna; Cleaves, II, H. James; Baddorf, Arthur P; Sumpter, Bobby G; Pan, Minghu; Maksymovych, Petro; et al

    2016-01-04

    The self-assembly of a nucleoside on Au(111) was studied to ascertain whether polymerization on well-defined substrates constitutes a promising approach for making sequence-controlled polymers. Scanning tunneling microscopy and density functional theory were used to investigate the self-assembly on Au(111) of (RS)-N9-(2,3-dihydroxypropyl)adenine (DHPA), a plausibly prebiotic nucleoside analog of adenosine. It is found that DHPA molecules self-assemble into a hydrogen-bonded polymer that grows almost exclusively along the herringbone reconstruction pattern, has a two component sequence that is repeated over hundreds of nanometers, and is erasable with electron-induced excitation. Although the sequence is simple, more complicated ones are envisioned if two ormore » more nucleoside types are combined. Because polymerization occurs on a substrate in a dry environment, the success of each combination can be gauged with high-resolution imaging and accurate modeling techniques. The resulting characteristics make nucleoside self-assembly on a substrate an attractive approach for designing sequence-controlled polymers. Moreover, by choosing plausibly prebiotic nucleosides, insights may be provided into how nature created the first sequence-controlled polymers capable of storing information. Such insights, in turn, can inspire new ways of synthesizing sequence-controlled polymers.« less

  16. Supramolecular polymerization of a prebiotic nucleoside provides insights into the creation of sequence-controlled polymers

    NASA Astrophysics Data System (ADS)

    Wang, Jun; Bonnesen, Peter V.; Rangel, E.; Vallejo, E.; Sanchez-Castillo, Ariadna; James Cleaves, H., II; Baddorf, Arthur P.; Sumpter, Bobby G.; Pan, Minghu; Maksymovych, Petro; Fuentes-Cabrera, Miguel

    2016-01-01

    Self-assembly of a nucleoside on Au(111) was studied to ascertain whether polymerization on well-defined substrates constitutes a promising approach for making sequence-controlled polymers. Scanning tunneling microscopy and density functional theory were used to investigate the self-assembly on Au(111) of (RS)-N9-(2,3-dihydroxypropyl)adenine (DHPA), a plausibly prebiotic nucleoside analog of adenosine. It is found that DHPA molecules self-assemble into a hydrogen-bonded polymer that grows almost exclusively along the herringbone reconstruction pattern, has a two component sequence that is repeated over hundreds of nanometers, and is erasable with electron-induced excitation. Although the sequence is simple, more complicated ones are envisioned if two or more nucleoside types are combined. Because polymerization occurs on a substrate in a dry environment, the success of each combination can be gauged with high-resolution imaging and accurate modeling techniques. These characteristics make nucleoside self-assembly on a substrate an attractive approach for designing sequence-controlled polymers. Further, by choosing plausibly prebiotic nucleosides, insights may be provided into how nature created the first sequence-controlled polymers capable of storing information. Such insights, in turn, can inspire new ways of synthesizing sequence-controlled polymers.

  17. Supramolecular polymerization of a prebiotic nucleoside provides insights into the creation of sequence-controlled polymers

    PubMed Central

    Wang, Jun; Bonnesen, Peter V.; Rangel, E.; Vallejo, E.; Sanchez-Castillo, Ariadna; James Cleaves II, H.; Baddorf, Arthur P.; Sumpter, Bobby G.; Pan, Minghu; Maksymovych, Petro; Fuentes-Cabrera, Miguel

    2016-01-01

    Self-assembly of a nucleoside on Au(111) was studied to ascertain whether polymerization on well-defined substrates constitutes a promising approach for making sequence-controlled polymers. Scanning tunneling microscopy and density functional theory were used to investigate the self-assembly on Au(111) of (RS)-N9-(2,3-dihydroxypropyl)adenine (DHPA), a plausibly prebiotic nucleoside analog of adenosine. It is found that DHPA molecules self-assemble into a hydrogen-bonded polymer that grows almost exclusively along the herringbone reconstruction pattern, has a two component sequence that is repeated over hundreds of nanometers, and is erasable with electron-induced excitation. Although the sequence is simple, more complicated ones are envisioned if two or more nucleoside types are combined. Because polymerization occurs on a substrate in a dry environment, the success of each combination can be gauged with high-resolution imaging and accurate modeling techniques. These characteristics make nucleoside self-assembly on a substrate an attractive approach for designing sequence-controlled polymers. Further, by choosing plausibly prebiotic nucleosides, insights may be provided into how nature created the first sequence-controlled polymers capable of storing information. Such insights, in turn, can inspire new ways of synthesizing sequence-controlled polymers. PMID:26725380

  18. Evaluating the reproducibility of quantifying modified nucleosides from ribonucleic acids by LC-UV-MS.

    PubMed

    Russell, Susan P; Limbach, Patrick A

    2013-04-01

    Post-transcriptional chemical covalent modification of adenosine, guanosine, uridine and cytidine occurs frequently in all types of ribonucleic acids (RNAs). In ribosomal RNA (rRNA) and transfer RNA (tRNA) these modifications make important contributions to RNA structure and stability and to the accuracy and efficiency of protein translation. The functional dynamics, synergistic nature and regulatory roles of these posttranscriptional nucleoside modifications within the cell are not well characterized. These modifications are present at very low levels and isolation of individual nucleosides for analysis requires a complex multi-step approach. The focus of this study is to characterize the reproducibility of a liquid chromatography method used to isolate and quantitatively characterize modified nucleosides in tRNA and rRNA when nucleoside detection is performed using ultraviolet and mass spectrometric detection (UV and MS, respectively). Despite the analytical challenges of sample isolation and dynamic range, quantitative profiling of modified nucleosides obtained from bacterial tRNAs and rRNAs is feasible at relative standard deviations of 5% RSD or less. PMID:23500350

  19. Supramolecular polymerization of a prebiotic nucleoside provides insights into the creation of sequence-controlled polymers.

    PubMed

    Wang, Jun; Bonnesen, Peter V; Rangel, E; Vallejo, E; Sanchez-Castillo, Ariadna; James Cleaves Ii, H; Baddorf, Arthur P; Sumpter, Bobby G; Pan, Minghu; Maksymovych, Petro; Fuentes-Cabrera, Miguel

    2016-01-01

    Self-assembly of a nucleoside on Au(111) was studied to ascertain whether polymerization on well-defined substrates constitutes a promising approach for making sequence-controlled polymers. Scanning tunneling microscopy and density functional theory were used to investigate the self-assembly on Au(111) of (RS)-N(9)-(2,3-dihydroxypropyl)adenine (DHPA), a plausibly prebiotic nucleoside analog of adenosine. It is found that DHPA molecules self-assemble into a hydrogen-bonded polymer that grows almost exclusively along the herringbone reconstruction pattern, has a two component sequence that is repeated over hundreds of nanometers, and is erasable with electron-induced excitation. Although the sequence is simple, more complicated ones are envisioned if two or more nucleoside types are combined. Because polymerization occurs on a substrate in a dry environment, the success of each combination can be gauged with high-resolution imaging and accurate modeling techniques. These characteristics make nucleoside self-assembly on a substrate an attractive approach for designing sequence-controlled polymers. Further, by choosing plausibly prebiotic nucleosides, insights may be provided into how nature created the first sequence-controlled polymers capable of storing information. Such insights, in turn, can inspire new ways of synthesizing sequence-controlled polymers. PMID:26725380

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

    PubMed Central

    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. PMID:26779190

  1. Transport of europium through supported liquid membrane containing dihexyl-N,N-diethyl-carbamoyl-methyl-phosphonate

    SciTech Connect

    Nakamura, Shigeto; Akiba, Kenichi )

    1989-12-01

    The transport of europium has been studied through a supported liquid membrane (SLM) impregnated with dihexyl-N,N-diethyl-carbamoyl-methyl-phosphonate (CMP). Europium was effectively extracted from the perchlorate solution into SLM, but was insufficiently stripped to a dilute acid solution. The addition of 1-decanol improved the stripping process, and quantitative transport of europium was achieved. By the combination of two SLM systems consisting of diisodecylphosphoric acid and CMP, europium was transported from the feed solution (0.1 M HNO{sub 3}) through the intermediate solution (1 M HClO{sub 4} + 4 M NaClO{sub 4}) to the product solution (0.1 M HNO{sub 3}) and effectively concentrated by a factor of about 20.

  2. Microwave assisted rapid synthesis of N-methylene phosphonic chitosan via Mannich-type reaction.

    PubMed

    Dadhich, Prabhash; Das, Bodhisatwa; Dhara, Santanu

    2015-11-20

    Bio-conjugation or functional group substitutions are well-explored methods to enhance the physico-chemical and biochemical functionality of chitosan. N-Methylene phosphonic chitosan (NMPC) is one of the major substituted forms of chitosan, which has significant bioactivity and promising biomedical application. However, the reported synthesis methods of NMPC have limitations alike poor yield, higher degradation rate and most importantly long synthesis time (∼14h). In the current study, rapid synthesis of NMPC via a Mannich type reaction route using microwave irradiation has been reported. This method of NMPC synthesis offers significantly less synthesis time with competitive product yield. Synthesized NMPC was characterized via NMR, FTIR, EDS, XRD and thermal analysis. Further, viscosity average molecular weight, solubility, and conductivity of the substituted polymer were measured. Preliminary cyto-compatibility results of synthesized NMPC were promising for further exploration in biomedical applications. PMID:26344290

  3. Syntheses, spectroscopic properties and stereochemistry of bis-C-pivot macrocycles with two dialkyl phosphonate groups

    NASA Astrophysics Data System (ADS)

    Bilge, Selen; Kılıç, Zeynel; Davies, David B.

    2011-10-01

    Bis-C-pivot macrocycles containing dimethyl ( 1a, 2a) or diethyl phosphonate ( 1b, 2b) groups have been prepared by adding dimethyl or diethyl phosphite to two -CH dbnd N bonds in corresponding dibenzo-bis-imino crown ethers ( 1 and 2). Bis-C-pivot macrocycles possess two equivalent stereogenic centres giving rise to diastereoisomers ( meso and racemate). The structures were characterized by elemental analysis, FTIR, MS, TGA, DSC and NMR measurements. 1H, 13C and 31P NMR assignments were made for the isolated meso form of compounds 2a and 2b and for the meso and racemic forms of compounds 1a and 1b by analysis of chemical shifts, signal intensities and splitting patterns and the DEPT and 2D HETCOR NMR techniques. Thermal analysis and 1H NMR showed that the crystallised form of compound 1a contained an equimolar amount of water of crystallisation.

  4. A report on emergent uranyl binding phenomena by an amidoxime phosphonic acid co-polymer.

    PubMed

    Abney, C W; Das, S; Mayes, R T; Kuo, L-J; Wood, J; Gill, G; Piechowicz, M; Lin, Z; Lin, W; Dai, S

    2016-09-14

    The development of technology to harvest the uranium dissolved in seawater would enable access to vast quantities of this critical metal for nuclear power generation. Amidoxime polymers are the most promising platforms for achieving this separation, yet the design of advanced adsorbents is hindered by uncertainty regarding the uranium binding mode. In this work we use XAFS to investigate the uranium coordination environment in an amidoxime-phosphonic acid copolymer adsorbent. In contrast to the binding mode predicted computationally and from small molecule studies, a cooperative chelating model is favoured, attributable to emergent behavior resulting from inclusion of amidoxime in the polymer. Samples exposed to seawater also display a feature consistent with a μ(2)-oxo-bridged transition metal, suggesting the formation of an in situ specific binding site. These findings challenge long held assumptions and provide new opportunities for the design of advanced adsorbent materials. PMID:27507226

  5. An ATR-FTIR study of different phosphonic acids adsorbed onto boehmite

    NASA Astrophysics Data System (ADS)

    Zenobi, María C.; Luengo, Carina V.; Avena, Marcelo J.; Rueda, Elsa H.

    2010-04-01

    An ATR-FTIR study of the vibrational spectra of N,N-bis(2-hydroxyethyl) aminomethylphosphonic acid (BHAMP), 1-hydroxyethane-1,1'-diphosphonic acid (HEDP) and nitrilotris(methylenephosphonic acid) (NTMP) adsorbed onto boehmite is presented. The study was performed in the pH range from 5 to 9, and bands assignments are given in the 1200-900 cm -1 wavenumber range, where the bands associated with various P-O(H) vibrations can be found. The three phosphonic acids adsorb onto boehmite by forming inner-sphere surface complexes. ATR-FTIR data indicates the presence of both protonated and deprotonated mononuclear surface species. In all cases, the surface-bound ions undergo protonation reactions as pH is decreased. The results are in good agreement with previously proposed surface complexation models.

  6. An ATR-FTIR study of different phosphonic acids adsorbed onto boehmite.

    PubMed

    Zenobi, María C; Luengo, Carina V; Avena, Marcelo J; Rueda, Elsa H

    2010-04-01

    An ATR-FTIR study of the vibrational spectra of N,N-bis(2-hydroxyethyl) aminomethylphosphonic acid (BHAMP), 1-hydroxyethane-1,1'-diphosphonic acid (HEDP) and nitrilotris(methylenephosphonic acid) (NTMP) adsorbed onto boehmite is presented. The study was performed in the pH range from 5 to 9, and bands assignments are given in the 1200-900 cm(-1) wavenumber range, where the bands associated with various P-O(H) vibrations can be found. The three phosphonic acids adsorb onto boehmite by forming inner-sphere surface complexes. ATR-FTIR data indicates the presence of both protonated and deprotonated mononuclear surface species. In all cases, the surface-bound ions undergo protonation reactions as pH is decreased. The results are in good agreement with previously proposed surface complexation models. PMID:20129815

  7. Enhanced cell affinity of poly( L-lactide) film by immobilizing phosphonized chitosan

    NASA Astrophysics Data System (ADS)

    Tian, Ye; Zhou, Chang-ren; Zeng, Qing-hui; Yang, Ju-lin; Han, Feng-xian; Tian, Jin-huan

    2008-11-01

    Graft polymerization of acrylic acid (AA) onto poly( L-lactide) (PLLA) film by UV irradiation was carried out to develop surfaces for N-methylene phosphonic chitosan (NMPC) immobilization. The properties of modified films were discussed by colorimetric method, attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR), contact angles, atomic force microscopy (AFM) and osteoblast incubation. The results showed that AA solution concentration and irradiation time had effect on the graft carboxyl densities. Comparing the ATR-FTIR images, two new peaks at 1561 cm -1 and 1632 cm -1 proved that NMPC was immobilized on the film surface successfully. The water contact-angles were decreased from 90 ± 5° to 37 ± 5° after modification. The AFM images indicated that the surface of the combined film was rougher than that of untreated film. The grafted film provided an excellent substrate for the growth of osteoblast.

  8. Synthesis, Cytotoxicity, DNA Binding and Apoptosis of Rhein-Phosphonate Derivatives as Antitumor Agents

    PubMed Central

    Ye, Man-Yi; Yao, Gui-Yang; Wei, Jing-Chen; Pan, Ying-Ming; Liao, Zhi-Xin; Wang, Heng-Shan

    2013-01-01

    Several rhein-phosphonate derivatives (5a–c) were synthesized and evaluated for in vitro cytotoxicity against HepG-2, CNE, Spca-2, Hela and Hct-116 cell lines. Some compounds showed relatively high cytotoxicity. Especially compounds 5b exhibited the strongest cytotoxicity against HepG-2 and Spca-2 cells (IC50 was 8.82 and 9.01 μM), respectively. All the synthesized compounds exhibited low cytotoxicity against HUVEC cells. Further experiments proved that 5b could disturb the cell cycle in HepG-2 cells and induce apoptosis. In addition, the binding properties of a model conjugate 5b to DNA were investigated by methods (UV-Vis, fluorescence, CD spectroscopy). Results indicated that 5b showed moderate ability to interact ct-DNA. PMID:23629673

  9. Isotopic Measurements of Sulphonates and Phosphonates and Investigations of Possible Formaldehyde Products from the Murchison Meteorite

    NASA Technical Reports Server (NTRS)

    Cooper, George

    1996-01-01

    Intramolecular carbon, hydrogen, and sulfur isotope measurements have been made on a homologous series of organic sulfonates discovered in the Murchison meteorite. Mass independent sulfur isotope fractionations were observed along with D/H ratios clearly larger than terrestrial. The sulfur fractionations may be produced chemically and due to molecular symmetry factors. The deuterium enrichments indicate formation of the hydrocarbon portion of these compounds in a low temperature astrophysical environment consistent with that of molecular clouds. The source of the sulfonate precursors may have been the reactive interstellar molecule, CS. Low temperature CS reactions also produce other sulfur containing compounds as well as a solid phase. Isotopic measurements on bulk phosphonates were also made.

  10. Paclitaxel-loaded phosphonated calixarene nanovesicles as a modular drug delivery platform

    PubMed Central

    Mo, Jingxin; Eggers, Paul K.; Yuan, Zhi-xiang; Raston, Colin L.; Lim, Lee Yong

    2016-01-01

    A modular p-phosphonated calix[4]arene vesicle (PCV) loaded with paclitaxel (PTX) and conjugated with folic acid as a cancer targeting ligand has been prepared using a thin film-sonication method. It has a pH-responsive capacity to trigger the release of the encapsulated PTX payload under mildly acidic conditions. PTX-loaded PCV conjugated with alkyne-modified PEG-folic acid ligands prepared via click ligation (fP-PCVPTX) has enhanced potency against folate receptor (FR)-positive SKOV-3 ovarian tumour cells over FR-negative A549 lung tumour cells. Moreover, fP-PCVPTX is also four times more potent than the non-targeting PCVPTX platform towards SKOV-3 cells. Overall, as a delivery platform the PCVs have the potential to enhance efficacy of anticancer drugs by targeting a chemotherapeutic payload specifically to tumours and triggering the release of the encapsulated drug in the vicinity of cancer cells. PMID:27009430

  11. A report on emergent uranyl binding phenomena by an amidoxime phosphonic acid co-polymer

    DOE PAGESBeta

    Abney, C. W.; Das, S.; Mayes, R. T.; Kuo, L. -J.; Wood, J.; Gill, G.; Piechowicz, M.; Lin, Z.; Lin, W.; Dai, S.

    2016-08-01

    Development of technology to harvest the uranium dissolved in seawater would enable access to vast quantities of this critical metal for nuclear power generation. Amidoxime polymers are the most promising platform for achieving this separation, yet design of advanced adsorbents is hindered by uncertainty regarding the uranium binding mode. In this work we use XAFS to investigate the uranium coordination environment in an amidoxime-phosphonic acid copolymer adsorbent. In contrast to the binding mode predicted computationally and from small molecule studies, a cooperative chelating model is favoured, attributable to emergent behavior resulting from inclusion of amidoxime in a polymer. Samples exposedmore » to seawater also display a feature consistent with a 2-oxo-bridged transition metal, suggesting formation of an in situ specific binding site. As a result, these findings challenge long held assumptions and provide new opportunities for the design of advanced adsorbent materials.« less

  12. Phosphonic analogues of tyrosine and 3,4-dihydroxyphenylalanine (dopa) influence mushroom tyrosinase activity.

    PubMed Central

    Lejczak, B; Kafarski, P; Makowiecka, E

    1987-01-01

    A series of phosphonic analogues of tyrosine and 3,4-dihydroxyphenylalanine (dopa) were synthesized in order to study their interaction with mushroom tyrosinase. 1-Amino-2-(3,4-dihydroxyphenyl)ethylphosphonic acid and 1-amino-2-(3,4-dimethoxyphenyl)ethylphosphonic acid turned out to be substrates for mushroom tyrosinase with Km values of 3.3 mM and 9.3 mM respectively. Shortening of the alkyl chain by one methylene group gave amino-(3,4-dihydroxyphenyl)methylphosphonic acid, one of the most powerful known inhibitors of this enzyme. This compound, racemic as well as in its optically active forms, exerts a mixed type of inhibition with an affinity for the enzyme one order of magnitude greater than that of the natural substrate. PMID:3109385

  13. Tunable thermal and flame response of phosphonated oligoallylamines layer by layer assemblies on cotton.

    PubMed

    Carosio, Federico; Negrell-Guirao, Claire; Di Blasio, Alessandro; Alongi, Jenny; David, Ghislain; Camino, Giovanni

    2015-01-22

    In the present paper we have demonstrated how the change of the layer by layer deposition parameters can influence the final properties of cotton fabrics in terms of coating morphology, thermal stability and flammability. To this aim, novel synthetized oligoallylamines and phosphonated oligoallylamines have been assembled on the surface of cotton exploiting different molecular weights and pH conditions. Low molecular weights have yielded an incomplete "island growth" coating while high molecular weight resulted in a homogeneous coating which thickness was controlled by the adopted pH. Both low and high molecular weight assemblies induced a reduction of the cellulose decomposition temperatures that was, conversely, delayed by coatings assembled at pH=10. All assemblies were able to improve cotton flammability by suppressing the afterglow phenomenon; the best results in terms of flame spread and final residue have been achieved by high molecular weight assemblies. PMID:25439958

  14. Alpha-heteroatom derivatized analogues of 3-(acetylhydroxyamino)propyl phosphonic acid (FR900098) as antimalarials.

    PubMed

    Verbrugghen, Thomas; Vandurm, Pierre; Pouyez, Jenny; Maes, Louis; Wouters, Johan; Van Calenbergh, Serge

    2013-01-10

    To explore the hitherto successful derivatization of the α-carbon of fosmidomycin, a series of new α-substituted analogues was prepared. This was done by introduction of a heteroatom (N or O) in α-position to the phosphonate and using the resultant OH and NH₂ groups as a handle for appending a variety of substituents by means of several functional groups such as ether, amide, urea, and 1,4-triazole. The synthesized molecules, as a racemic mixture, were assayed for their EcDXR inhibitory potency. Both the α-azido-analogue and the α-hydroxylated analogue proved most promising, and docking experiments were performed. Although several compounds showed high potency when assayed against Plasmodium falciparum K1 in human erythrocytes, a clear correlation between the enzyme inhibition constants and P. falciparum inhibition concentrations could not be found. PMID:23215035

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

    PubMed

    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

  16. Solid-State NMR Characterization of Mixed Phosphonic Acid Ligand Binding and Organization on Silica Nanoparticles.

    PubMed

    Davidowski, Stephen K; Holland, Gregory P

    2016-04-01

    As ligand functionalization of nanomaterials becomes more complex, methods to characterize the organization of multiple ligands on surfaces is required. In an effort to further the understanding of ligand-surface interactions, a combination of multinuclear ((1)H, (29)Si, (31)P) and multidimensional solid-state nuclear magnetic resonance (NMR) techniques was utilized to characterize the phosphonic acid functionalization of fumed silica nanoparticles using methylphosphonic acid (MPA) and phenylphosphonic acid (PPA). (1)H → (29)Si cross-polarization (CP)-magic angle spinning (MAS) solid-state NMR was used to selectively detect silicon atoms near hydrogen atoms (primarily surface species); these results indicate that geminal silanols are preferentially depleted during the functionalization with phosphonic acids. (1)H → (31)P CP-MAS solid-state NMR measurements on the functionalized silica nanoparticles show three distinct resonances shifted upfield (lower ppm) and broadened compared to the resonances of the crystalline ligands. Quantitative (31)P MAS solid-state NMR measurements indicate that ligands favor a monodentate binding mode. When fumed silica nanoparticles were functionalized with an equal molar ratio of MPA and PPA, the MPA bound the nanoparticle surface preferentially. Cross-peaks apparent in the 2D (1)H exchange spectroscopy (EXSY) NMR measurements of the multiligand sample at short mixing times indicate that the MPA and PPA are spatially close (≤5 Å) on the surface of the nanostructure. Furthermore, (1)H-(1)H double quantum-single quantum (DQ-SQ) back-to-back (BABA) 2D NMR spectra further confirmed that MPA and PPA are strongly dipolar coupled with observation of DQ intermolecular contacts between the ligands. DQ experimental buildup curves and simulations indicate that the average distance between MPA and PPA is no further than 4.2 ± 0.2 Å. PMID:26914738

  17. The role of minerals in the thermal alteration of organic matter. IV - Generation of n-alkanes, acyclic isoprenoids, and alkenes in laboratory experiments

    NASA Technical Reports Server (NTRS)

    Huizinga, Bradley J.; Tannenbaum, Eli; Kaplan, Isaac R.

    1987-01-01

    The effect of common sedimentary minerals (illite, Na-montmorillonite, or calcite) under different water concentrations on the generation and release of n-alkanes, acyclic isoprenoids, and select alkenes from oil-prone kerogens was investigated. Matrices containing Green River Formation kerogen or Monterey Formation kerogen, alone or in the presence of minerals, were heated at 200 or 300 C for periods of up to 1000 hours, and the pyrolysis products were analyzed. The influence of the first two clay minerals was found to be critically dependent on the water content. Under the dry pyrolysis conditions, both minerals significantly reduced alkene formation; the C12+ n-alkanes and acyclic isoprenoids were mostly destroyed by montmorillonite, but underwent only minor alteration with illite. Under hydrous conditions (mineral/water of 2/1), the effects of both minerals were substantially reduced. Calcite had no significant effect on the thermal evolution of the hydrocarbons.

  18. Probing the TRAP-RNA interaction with nucleoside analogs.

    PubMed

    Elliott, M B; Gottlieb, P A; Gollnick, P

    1999-10-01

    The trp RNA-binding Attenuation Protein (TRAP) from Bacillus subtilis binds a series of GAG and UAG repeats separated by 2-3 nonconserved spacer nucleotides in trp leader mRNA. To identify chemical groups on the RNA required for stability of the TRAP-RNA complex, we introduced several different nucleoside analogs into each pentamer of the RNA sequence 5'-(UAGCC)-3' repeated 11 times and measured their effect on the TRAP-RNA interaction. Deoxyribonucleoside substitutions revealed that a 2'-hydroxyl group (2'-OH) is required only on the guanosine occupying the third residue of the RNA triplets for high-affinity binding to TRAP. The remaining hydroxyl groups are dispensable. Base analog substitutions identified all of the exocyclic functional groups and N1 nitrogens of adenine and guanine in the second and third nucleotides, respectively, of the triplets as being involved in binding TRAP. In contrast, none of the substitutions made in the first residue caused any detectable changes in affinity, indicating that elements of these bases are not necessary for complex formation and stability. Studies using abasic nucleotides in the first residue of the triplets and in the two spacer residues confirmed that the majority of the specificity and stability of the TRAP-RNA complex is provided by the AG dinucleotide of the triplet repeats. In addition to direct effects on binding, we demonstrate that the N7-nitrogen of adenosine and guanosine in UAG triplet and the 2'-OHs of (UAGCC)11 RNA are involved in the formation of an as yet undetermined structure that interferes with TRAP binding. PMID:10573119

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

    PubMed

    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

  20. Analysis of UDP-D-apiose/UDP-D-xylose synthase-catalyzed conversion of UDP-D-apiose phosphonate to UDP-D-xylose phosphonate: implications for a retroaldol-aldol mechanism.

    PubMed

    Choi, Sei-hyun; Mansoorabadi, Steven O; Liu, Yung-nan; Chien, Tun-Cheng; Liu, Hung-wen

    2012-08-29

    UDP-D-apiose/UDP-D-xylose synthase (AXS) catalyzes the conversion of UDP-D-glucuronic acid to UDP-D-apiose and UDP-D-xylose. An acetyl-protected phosphonate analogue of UDP-D-apiose was synthesized and used in an in situ HPLC assay to demonstrate for the first time the ability of AXS to interconvert the two reaction products. Density functional theory calculations provided insight into the energetics of this process and the apparent inability of AXS to catalyze the conversion of UDP-D-xylose to UDP-D-apiose. The data suggest that this observation is unlikely to be due to an unfavorable equilibrium but rather results from substrate inhibition by the most stable chair conformation of UDP-D-xylose. The detection of xylose cyclic phosphonate as the turnover product reveals significant new details about the AXS-catalyzed reaction and supports the proposed retroaldol-aldol mechanism of catalysis. PMID:22830643

  1. The concentrative nucleoside transporter family (SLC28): new roles beyond salvage?

    PubMed

    Aymerich, I; Duflot, S; Fernández-Veledo, S; Guillén-Gómez, E; Huber-Ruano, I; Casado, F J; Pastor-Anglada, M

    2005-02-01

    The concentrative nucleoside transporter (CNT) family (SLC28) has three members: SLC28A1 (CNT1), SLC28A2 (CNT2) and SLC28A3 (CNT3). The CNT1 and CNT2 transporters are co-expressed in liver parenchymal cells and macrophages, two suitable models in which to study cell cycle progression. Despite initial observations suggesting that these transporter proteins might contribute to nucleoside salvage during proliferation, their subcellular localization and regulatory properties suggest alternative roles in cell physiology. In particular, CNT2 is a suitable candidate for modulation of purinergic responses, since it is under the control of the adenosine 1 receptor. Increasing evidence also suggests a role for CNT2 in energy metabolism, since its activation relies on the opening of ATP-sensitive K(+) channels. Animal and cell models genetically modified to alter nucleoside transporter expression levels may help to elucidate the particular roles of CNT proteins in cell physiology. PMID:15667311

  2. Transition State Analogues of Purine Nucleoside Phosphorylase: the Work of Vernon L. Schramm

    PubMed Central

    Kresge, Nicole; Simoni, Robert D.; Hill, Robert L.

    2010-01-01

    Transition State Analogue Inhibitors of Purine Nucleoside Phosphorylase from Plasmodium falciparum (Kicska, G. A., Tyler, P. C., Evans, G. B., Furneaux, R. H., Kim, K., and Schramm, V. L. (2002) J. Biol. Chem. 277, 3219–3225) Purine-less Death in Plasmodium falciparum Induced by Immucillin-H, a Transition State Analogue of Purine Nucleoside Phosphorylase (Kicska, G. A., Tyler, P. C., Evans, G. B., Furneaux, R. H., Schramm, V. L., and Kim, K. (2002) J. Biol. Chem. 277, 3226–3231) Achieving the Ultimate Physiological Goal in Transition State Analogue Inhibitors for Purine Nucleoside Phosphorylase (Lewandowicz, A., Tyler, P. C., Evans, G. B., Furneaux, R. H., and Schramm, V. L. (2003) J. Biol. Chem. 278, 31465–31468)

  3. Conformational analysis of a nucleoside of 1,4-dihydro-4-oxoquinoline-3-carboxylic acid analogue

    NASA Astrophysics Data System (ADS)

    Zaccur Leal, Kátia; Rudolf Seidl, Peter; Diniz Yoneda, Julliane; Santos, CarlaV. B.; Marques, Isakelly P.; Souza, Maria Cecília B. V.; Francisco Ferreira, Vitor

    2005-06-01

    The synthesis of new ribonucleosides is an essential research area in the investigation of new therapeutically useful agents, particularly those used in the treatment of HIV infection. The conformation of these nucleosides may have direct implications for their ability to bind to receptor targets. We have prepared the 7-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid derivatives and used the ensemble of low-energy minima to develop conformational profiles of quinolonic nucleosides and verify their accuracy in different calculations of structural parameters. Results are compared with experimental data obtained by X-ray and NMR analysis. Finally, we intend to test the applicability of these methods to conformational analysis of other nucleosides and verify if the preferential conformation is the one which gives the best anti-HIV or antiviral activity.

  4. Structural and Enzymatic Characterization of a Nucleoside Diphosphate Sugar Hydrolase from Bdellovibrio bacteriovorus

    PubMed Central

    Duong-ly, Krisna C.; Schoeffield, Andrew J.; Pizarro-Dupuy, Mario A.; Zarr, Melissa; Pineiro, Silvia A.; Amzel, L. Mario; Gabelli, Sandra B.

    2015-01-01

    Given the broad range of substrates hydrolyzed by Nudix (nucleoside diphosphate linked to X) enzymes, identification of sequence and structural elements that correctly predict a Nudix substrate or characterize a family is key to correctly annotate the myriad of Nudix enzymes. Here, we present the structure determination and characterization of Bd3179 –- a Nudix hydrolase from Bdellovibrio bacteriovorus–that we show localized in the periplasmic space of this obligate Gram-negative predator. We demonstrate that the enzyme is a nucleoside diphosphate sugar hydrolase (NDPSase) and has a high degree of sequence and structural similarity to a canonical ADP-ribose hydrolase and to a nucleoside diphosphate sugar hydrolase (1.4 and 1.3 Å Cα RMSD respectively). Examination of the structural elements conserved in both types of enzymes confirms that an aspartate-X-lysine motif on the C-terminal helix of the α-β-α NDPSase fold differentiates NDPSases from ADPRases. PMID:26524597

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

    SciTech Connect

    Grenha, Rosa; Levdikov, Vladimir M.; Fogg, Mark J.; Blagova, Elena V.; Brannigan, James A. Wilkinson, Anthony J.; Wilson, Keith S.

    2005-05-01

    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.

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

    PubMed

    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

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

    PubMed Central

    Hens, Marc; Vaidyanathan, Ganesan; Zhao, Xiao-Guang; Bigner, Darell D.; Zalutsky, Michael R.

    2010-01-01

    Introduction Monoclonal antibody (mAb) L8A4 binds specifically to the epidermal growth factor receptor variant III (EGFRvIII) that is present on gliomas but not normal tissues, and is internalized rapidly after receptor binding. Because of the short range of its β-emissions, labeling this mAb with177Lu 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 177Lu 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 α-(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.)EGFR glioma xenografts over a period of 1 to 8 days to directly compare 177Lu-labeled L8A4 to L8A4 labeled with 125I using N-succinimidyl 4-guanidinomethyl-3-[125I]iodobenzoate ([125I]SGMIB). Results Except with C-DOTA, tumor uptake for the 177Lu-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 177Lu-1B4M-DTPA-L8A4 and to an even greater extent, 177Lu-MeO-DOTA-L8A4, were higher than those for [125I]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 177Lu labeling. Optimal results were obtained with 1B4M-DTPA and MeO-DOTA, suggesting no clear advantage for acyclic vs. macrocyclic ligands for this application. PMID:20870149

  8. Analysis of cyclic and acyclic nicotinic cholinergic agonists using radioligand binding, single channel recording, and nuclear magnetic resonance spectroscopy.

    PubMed Central

    McGroddy, K A; Carter, A A; Tubbert, M M; Oswald, R E

    1993-01-01

    The relationship between the structure and function of a series of nicotinic cholinergic agonists has been studied using radioligand binding, single channel recording, and nuclear magnetic resonance spectroscopy. The cyclic compound 1,1-dimethyl-4-acetylpiperazinium iodide and its trifluoromethyl analogue (F3-PIP) interact with nicotinic acetylcholine receptors (nAChRs) from both Torpedo electroplaque and BC3H-1 cells at lower concentrations than the acyclic derivatives, N,N,N,N'-tetramethyl-N'-acetylethylenediamine iodide and its fluorinated analogue (F3-TED). The magnitude of the difference in potencies depends on the type of measurement. In binding experiments, the differences between the two classes of compounds depends mainly on the conditions of the experiment. In measurements of the initial interaction with the nAChR, the PIP compounds have an affinity approximately one order of magnitude higher than that of the TED compounds. Longer incubations indicated that the PIP compounds were able to induce a time-dependent shift in receptor affinity consistent with desensitization, whereas the TED compounds were unable to induce such a shift. The activation of single channel currents by the cyclic compounds occurs at concentrations approximately two orders of magnitude lower than for the acyclic compounds, but the TED compounds exhibit a larger degree of channel blockade than the PIP compounds. Previous work (McGroddy, K.A., and R.E. Oswald. 1992. Biophys. J. 64:314-324) has shown that the TED compounds can exist in two energetically distinct conformational states related by an isomerization of the amide bond. 19F nuclear magnetic resonance experiments suggest that the higher energy population of the TED compounds may interact preferentially with the ACh binding sites on the nAChRs and that a significant fraction of the difference between the initial affinity of the PIP and TED compounds may be accounted for by the predominance in solution of a conformational state

  9. Functional and genetic diversity in the concentrative nucleoside transporter, CNT1, in human populations.

    PubMed

    Gray, Jennifer H; Mangravite, Lara M; Owen, Ryan P; Urban, Thomas J; Chan, Wendy; Carlson, Elaine J; Huang, Conrad C; Kawamoto, Michiko; Johns, Susan J; Stryke, Douglas; Ferrin, Thomas E; Giacomini, Kathleen M

    2004-03-01

    The concentrative nucleoside transporter, CNT1 (SLC28A1), mediates the cellular uptake of naturally occurring pyrimidine nucleosides and many structurally diverse anticancer and antiviral nucleoside analogs. As a first step toward understanding whether genetic variation in CNT1 contributes to variation in the uptake and disposition of clinically used nucleoside analogs, we determined the haplotype structure and functionally analyzed all coding region variants of CNT1 identified in ethnically diverse populations (100 African Americans, 100 European Americans, 30 Asians, 10 Mexican Americans, and 7 Pacific Islanders) (Leabman et al., 2003). A total of 58 coding region haplotypes were identified using PHASE analysis, 44 of which contained at least one amino acid variant. More than half of the coding region haplotypes were population-specific. Using site-directed mutagenesis, 15 protein-altering CNT1 variants, including one amino acid insertion and one base pair (bp) deletion, were constructed and expressed in Xenopus laevis oocytes. All variant transporters took up [3H]thymidine with the exception of CNT1-Ser546Pro, a rare variant, and CNT1-1153del, a single bp deletion found at a frequency of 3% in the African American population. The bp deletion results in a frame-shift followed by a stop-codon. The anticancer nucleoside analog gemcitabine had a reduced affinity for CNT1-Val189Ile (a common CNT1 variant found at a frequency of 26%) compared with reference CNT1 (IC50=13.8 +/- 0.60 microM for CNT1-reference and 23.3 +/- 1.5 microM for CNT1-Val189Ile, p<0.05). These data suggest that common genetic variants of CNT1 may contribute to variation in systemic and intracellular levels of anti-cancer nucleoside analogs. PMID:14978229

  10. Characterization of intestinal absorption of mizoribine mediated by concentrative nucleoside transporters in rats.

    PubMed

    Mori, Nobuhiro; Yokooji, Tomoharu; Kamio, Yoshihiro; Murakami, Teruo

    2008-05-31

    Mizoribine, an imidazole nucleoside, is an inhibitor of purine synthesis and has been used as an orally available immunosuppressive agent in human renal transplantation. In the present study, the intestinal absorption of mizoribine was characterized by examining the contribution of concentrative nucleoside transporters (CNT1, CNT2) in rats. When mizoribine was administered orally in conscious rats, the bioavailability of mizoribine estimated by urinary excretion percentage of unchanged mizoribine was a dose dependent: 53.1+/-6.0% at 5 mg/kg and 24.0+/-5.1% at 20 mg/kg. In in-situ loop studies, the disappearance rate, or absorption rate, of mizoribine from the intestinal lumen was comparable between 1 and 5 mg/kg, but significantly lower at 25 mg/kg. Coadministration of adenosine (a substrate of both CNT1 and CNT2), thymidine (a CNT1 substrate) and inosine (a CNT2 substrate) significantly suppressed the intestinal mizoribine absorption, depending on the nucleoside concentrations coadministered. Gemcitabine (a pyrimidine nucleoside analogue, a CNT1 substrate) and ribavirin (a purine nucleoside analog, a CNT2 substrate) also significantly suppressed the mizoribine intestinal absorption. Bile salts such as sodium cholate and sodium glycocholate (10 mM) also significantly suppressed the intestinal mizoribine absorption, but not ribavirin absorption. Mizoribine is an amphoteric compound, however, the suppression of intestinal absorption by bile salts was not ascribed to the electrostatic interaction or micellar formation between mizoribine and bile salts. In conclusion, the intestinal absorption of mizoribine is mediated by CNT1 and CNT2, and nucleoside-derived drugs such as gemcitabine and ribavirin can suppress the intestinal absorption of mizoribine. Bile salts such as sodium glycocholate were also found to cause interaction with mizoribine. PMID:18371949

  11. Nucleoside transporter proteins as biomarkers of drug responsiveness and drug targets

    PubMed Central

    Pastor-Anglada, Marçal; Pérez-Torras, Sandra

    2015-01-01

    Nucleoside and nucleobase analogs are currently used in the treatment of solid tumors, lymphoproliferative diseases, viral infections such as hepatitis and AIDS, and some inflammatory diseases such as Crohn. Two gene families are implicated in the uptake of nucleosides and nucleoside analogs into cells, SCL28 and SLC29. The former encodes hCNT1, hCNT2, and hCNT3 proteins. They translocate nucleosides in a Na+ coupled manner with high affinity and some substrate selectivity, being hCNT1 and hCNT2 pyrimidine- and purine-preferring, respectively, and hCNT3 a broad selectivity transporter. SLC29 genes encode four members, being hENT1 and hENT2 the only two which are unequivocally implicated in the translocation of nucleosides and nucleobases (the latter mostly via hENT2) at the cell plasma membrane. Some nucleoside-derived drugs can also interact with and be translocated by members of the SLC22 gene family, particularly hOCT and hOAT proteins. Inter-individual differences in transporter function and perhaps, more importantly, altered expression associated with the disease itself might modulate the transporter profile of target cells, thereby determining drug bioavailability and action. Drug transporter pharmacology has been periodically reviewed. Thus, with this contribution we aim at providing a state-of-the-art overview of the clinical evidence generated so far supporting the concept that these membrane proteins can indeed be biomarkers suitable for diagnosis and/or prognosis. Last but not least, some of these transporter proteins can also be envisaged as drug targets, as long as they can show “transceptor” functions, in some cases related to their role as modulators of extracellular adenosine levels, thereby providing a functional link between P1 receptors and transporters. PMID:25713533

  12. Isolation and functional characterization of the PfNT1 nucleoside transporter gene from Plasmodium falciparum.

    PubMed

    Carter, N S; Ben Mamoun, C; Liu, W; Silva, E O; Landfear, S M; Goldberg, D E; Ullman, B

    2000-04-01

    Plasmodium falciparum, the causative agent of the most lethal form of human malaria, is incapable of de novo purine synthesis, and thus, purine acquisition from the host is an indispensable nutritional requirement. This purine salvage process is initiated by the transport of preformed purines into the parasite. We have identified a gene encoding a nucleoside transporter from P. falciparum, PfNT1, and analyzed its function and expression during intraerythrocytic parasite development. PfNT1 predicts a polypeptide of 422 amino acids with 11 transmembrane domains that is homologous to other members of the equilibrative nucleoside transporter family. Southern analysis and BLAST searching of The Institute for Genomic Research (TIGR) malaria data base indicate that PfNT1 is a single copy gene located on chromosome 14. Northern analysis of RNA from intraerythrocytic stages of the parasite demonstrates that PfNT1 is expressed throughout the asexual life cycle but is significantly elevated during the early trophozoite stage. Functional expression of PfNT1 in Xenopus laevis oocytes significantly increases their ability to take up naturally occurring D-adenosine (K(m) = 13.2 microM) and D-inosine (K(m) = 253 microM). Significantly, PfNT1, unlike the mammalian nucleoside transporters, also has the capacity to transport the stereoisomer L-adenosine (K(m) > 500 microM). Inhibition studies with a battery of purine and pyrimidine nucleosides and bases as well as their analogs indicate that PfNT1 exhibits a broad substrate specificity for purine and pyrimidine nucleosides. These data provide compelling evidence that PfNT1 encodes a functional purine/pyrimidine nucleoside transporter whose expression is strongly developmentally regulated in the asexual stages of the P. falciparum life cycle. Moreover, the unusual ability to transport L-adenosine and the vital contribution of purine transport to parasite survival makes PfNT1 an attractive target for therapeutic evaluation. PMID

  13. Evidence for incorporation of intact dietary pyrimidine (but not purine) nucleosides into hepatic RNA.

    PubMed Central

    Berthold, H K; Crain, P F; Gouni, I; Reeds, P J; Klein, P D

    1995-01-01

    The absorption and metabolism of dietary nucleic acids have received less attention than those of other organic nutrients, largely because of methodological difficulties. We supplemented the rations of poultry and mice with the edible alga Spirulina platensis, which had been uniformly labeled with 13C by hydroponic culture in 13CO2. The rations were ingested by a hen for 4 wk and by four mice for 6 days; two mice were fed a normal diet and two were fed a nucleic acid-deficient diet. The animals were killed and nucleosides were isolated from hepatic RNA. The isotopic enrichment of all mass isotopomers of the nucleosides was analyzed by selected ion monitoring of the negative chemical ionization mass spectrum and the labeling pattern was deconvoluted by reference to the enrichment pattern of the tracer material. We found a distinct difference in the 13C enrichment pattern between pyrimidine and purine nucleosides; the isotopic enrichment of uniformly labeled [M + 9] isotopomers of pyrimidines exceeded that of purines [M + 10] by > 2 orders of magnitude in the avian nucleic acids and by 7- and 14-fold in the murine nucleic acids. The purines were more enriched in lower mass isotopomers, those less than [M + 3], than the pyrimidines. Our results suggest that large quantities of dietary pyrimidine nucleosides and almost no dietary purine nucleosides are incorporated into hepatic nucleic acids without hydrolytic removal of the ribose moiety. In addition, our results support a potential nutritional role for nucleosides and suggest that pyrimidines are conditionally essential organic nutrients. PMID:7479738

  14. Correlation of nucleoside and nucleobase transporter gene expression with antimetabolite drug cytotoxicity.

    PubMed

    Lu, Xin; Gong, Shimei; Monks, Anne; Zaharevitz, Daniel; Moscow, Jeffrey A

    2002-01-01

    Antimetabolite drugs that inhibit nucleic acid metabolism are widely used in cancer chemotherapy. Nucleoside and nucleobase transporters are important for the cellular uptake of nucleic acids and their corresponding anticancer analogue drugs. Thus, these transporters may play a role both in antimetabolite drug sensitivity, by mediating the uptake of nucleoside analogues, and in antimetabolite drug resistance, by mediating the uptake of endogenous nucleosides that may rescue cells from toxicity. Therefore, we examined the relation of the expression of nucleoside and nucleobase transporters to antimetabolite cytotoxicity. We measured the RNA levels of all eight known nucleoside and nucleobase transporters in 50 cell lines included in the National Cancer Institute's Anticancer Drug Screen panel. RNA levels of concentrative nucleoside transporters (CNTs), equilibrative nucleoside transporters (ENTs) and nucleobase transporters (NCBTs) were determined by quantitative RT-PCR using real-time fluorescence acquisition. This method was validated by measuring the expression of the MDR1 gene, and correlating our results with independently determined measurements of MDR1 RNA levels and protein function in these cell lines. We then correlated the pattern of RNA levels to the pattern of cytotoxicity of anticancer drugs in the NCI drug screen database using the COMPARE analysis. Several hypothesized relations between transporter gene expression and cytotoxicity, based upon known interactions between certain nucleoside analogues and transporter proteins, were not observed, suggesting that expression of individual transporters may not be a significant determinant of the cytotoxicity of these drugs. The most closely correlated drug cytotoxicity patterns to transporter gene expression patterns (where increased expression corresponds to increase sensitivity) included those between CNT1 and O6-methylguanine and between ENT2 and hydroxyurea. We also observed that p53 status influenced

  15. Distribution of the modified nucleoside Q and its derivatives in animal and plant transfer RNA's.

    PubMed Central

    Kasai, H; Kuchino, Y; Nihei, K; Nishimura, S

    1975-01-01

    The modified nucleoside, 7-(4,5-cis-dihydroxy-1-cyclopenten-3-yl-aminomethyl)-7-deazaguanosine, designated as Q, and its derivative, Q*, were found in tRNA's from various organisms, including several mammalian tissues, other animals such as starfish, lingula and hagfish, and wheat germ. Q isolated from rat liver tRNA was found to be identical with E. coli Q by mass spectrometry and thin-layer chromatography. Thus the rare modified nucleoside Q originally isolated from E. coli tRNA, is widely distributed in various organisms. Analysis of the mass spectrum of Q* suggested that it has a different side chain from Q. PMID:1187350

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

    PubMed Central

    Grenha, Rosa; Levdikov, Vladimir M.; Fogg, Mark J.; Blagova, Elena V.; Brannigan, James A.; Wilkinson, Anthony J.; Wilson, Keith S.

    2005-01-01

    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. PMID:16511068

  17. Synthesis of optically pure dioxolane nucleosides and their anti-HIV activity

    SciTech Connect

    Siddigui, M.A.; Evans, C.; Jin, H.L.; Tse, A.; Brown, W.; Nguyen-Ba, N.; Mansour, T.S.; Cameron, J.M.

    1993-12-31

    The clinical candidate 3TC, 1, possessing non-natural absolute stereochemistry is a potent and non-toxic inhibitor of a key enzyme, reverse transcriptase, involved in the replicative cycle of the HIV. Selective inhibition of both HIV and HBV is seen. In view of the authors` interest in finding correlation between stereochemistry and antiviral activity, several enantiomerically pure dioxolane nucleosides, 2, were synthesized and assayed. The discussion will focus on (a) the synthesis of optically pure dioxolane sugars from L-ascorbic acid, (b) enzymatic resolution of purine dioxolane nucleosides, (c) anti HIV-1 activity in MT-4 cells.

  18. Synthesis and in vitro growth inhibitory activity of novel silyl- and trityl-modified nucleosides.

    PubMed

    Panayides, Jenny-Lee; Mathieu, Véronique; Banuls, Laetitia Moreno Y; Apostolellis, Helen; Dahan-Farkas, Nurit; Davids, Hajierah; Harmse, Leonie; Rey, M E Christine; Green, Ivan R; Pelly, Stephen C; Kiss, Robert; Kornienko, Alexander; van Otterlo, Willem A L

    2016-06-15

    Seventeen silyl- and trityl-modified (5'-O- and 3',5'-di-O-) nucleosides were synthesized with the aim of investigating the in vitro antiproliferative activities of these nucleoside derivatives. A subset of the compounds was evaluated at a fixed concentration of 100μM against a small panel of tumor cell lines (HL-60, K-562, Jurkat, Caco-2 and HT-29). The entire set was also tested at varying concentrations against two human glioma lines (U373 and Hs683) to obtain GI50 values, with the best results being values of ∼25μM. PMID:27157005

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

    NASA Astrophysics Data System (ADS)

    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.

  20. Structure and Mechanism of Enzymes Involved in Biosynthesis and Breakdown of the Phosphonates Fosfomycin, Dehydrophos, and Phosphinothricin

    PubMed Central

    Nair, Satish K.; van der Donk, Wilfred A.

    2011-01-01

    Recent years have seen a rapid increase in the mechanistic and structural information on enzymes that are involved in the biosynthesis and breakdown of naturally occurring phosphonates. This review focuses on these recent developments with an emphasis on those enzymes that have been characterized crystallographically in the past five years, including proteins involved in the biosynthesis of phosphinothricin, fosfomycin, and dehydrophos and proteins involved in resistance mechanisms. PMID:20854789

  1. Synthesis, spectroscopic and biological activities studies of acyclic and macrocyclic mono and binuclear metal complexes containing a hard-soft Schiff base

    NASA Astrophysics Data System (ADS)

    Abou-Hussein, Azza A. A.; Linert, Wolfgang

    Mono- and bi-nuclear acyclic and macrocyclic complexes with hard-soft Schiff base, H2L, ligand derived from the reaction of 4,6-diacetylresorcinol and thiocabohydrazide, in the molar ratio 1:2 have been prepared. The H2L ligand reacts with Co(II), Ni(II), Cu(II), Zn(II), Mn(II) and UO2(VI) nitrates, VO(IV) sulfate and Ru(III) chloride to get acyclic binuclear complexes except for VO(IV) and Ru(III) which gave acyclic mono-nuclear complexes. Reaction of the acyclic mono-nuclear VO(IV) and Ru(III) complexes with 4,6-diacetylresorcinol afforded the corresponding macrocyclic mono-nuclear VO(IV) and Ru(IIII) complexes. Template reactions of the 4,6-diacetylresorcinol and thiocarbohydrazide with either VO(IV) or Ru(III) salts afforded the macrocyclic binuclear VO(IV) and Ru(III) complexes. The Schiff base, H2L, ligand acts as dibasic with two NSO-tridentate sites and can coordinate with two metal ions to form binuclear complexes after the deprotonation of the hydrogen atoms of the phenolic groups in all the complexes, except in the case of the acyclic mononuclear Ru(III) and VO(IV) complexes, where the Schiff base behaves as neutral tetradentate chelate with N2S2 donor atoms. The ligands and the metal complexes were characterized by elemental analysis, IR, UV-vis 1H-NMR, thermal gravimetric analysis (TGA) and ESR, as well as the measurements of conductivity and magnetic moments at room temperature. Electronic spectra and magnetic moments of the complexes indicate the geometries of the metal centers are either tetrahedral, square planar or octahedral. Kinetic and thermodynamic parameters were calculated using Coats-Redfern equation, for the different thermal decomposition steps of the complexes. The ligands and the metal complexes were screened for their antimicrobial activity against Staphylococcus aureus as Gram-positive bacteria, and Pseudomonas fluorescens as Gram-negative bacteria in addition to Fusarium oxysporum fungus. Most of the complexes exhibit mild

  2. Synthesis and kinetic evaluation of Cyclophostin and Cyclipostins phosphonate analogs as selective and potent inhibitors of microbial lipases

    PubMed Central

    Point, Vanessa; Malla, Raj K.; Diomande, Sadia; Martin, Benjamin P.; Delorme, Vincent; Carriere, Frederic; Canaan, Stephane; Rath, Nigam P.; Spilling, Christopher D.; Cavalier, Jean-François

    2012-01-01

    New series of customizable diastereomeric cis- and trans-monocyclic enol-phosphonate analogs to Cyclophostin and Cyclipostins were synthesized. Their potencies and mechanisms of inhibition toward six representative lipolytic enzymes belonging to distinct lipase families were examined. With mammalian gastric and pancreatic lipases no inhibition occurred with any of the compounds tested. Conversely, Fusarium solani Cutinase and lipases from Mycobacterium tuberculosis (Rv0183 and LipY) were all fully inactivated. Best inhibitors displayed a cis conformation (H and OMe) and exhibited higher inhibitory activities than the lipase inhibitor Orlistat towards same enzymes. Our results have revealed that chemical group at the γ-carbon of the phosphonate ring strongly impacts the inhibitory efficiency, leading to a significant improvement in selectivity toward a target lipase over another. The powerful and selective inhibition of microbial (fungal and mycobacterial) lipases suggests that these 7-membered monocyclic enol-phosphonates should provide useful leads for the development of novel and highly selective antimicrobial agents. PMID:23095026

  3. 5-(1-Substituted) alkyl pyrimidine nucleosides as antiviral (herpes) agents.

    PubMed

    Kumar, Rakesh

    2004-10-01

    The treatment of viral diseases remains one of the major challenges to modern medicine. During the past two decades there has been increased recognition of the consequences of serious viral illnesses that are not controlled by vaccination. These illnesses include human immunodeficiency virus, human herpes viruses, and viruses that cause hepatitis. There are now eight pathogens recognized in the herpes virus family that cause infections in humans. Infections by the herpes viruses are opportunistic and often life-threatening, leading to significant morbidity and mortality in the increasing number of chronically immune compromised individuals such as AIDS patients, cancer patients and transplant recipients on immunosuppressive therapy. Nearly all individuals with AIDS are infected with one or more of the herpes viruses. Antiviral therapy with guanosine nucleoside analogs acyclovir and ganciclovir has had a major impact on diseases caused by herpes simplex virus type-1 and type-2 (HSV-1, HSV-2), Varicella zoster virus (VZV), and human cytomegalovirus (HCMV) but development of resistant virus strains and the absence of any effective treatment for other members of the herpes family provide a stimulus for increased search of new agents effective against various herpes viruses. Pyrimidine nucleosides have taken up an important role in the therapy of virus infection. Significant progress in the study of anti-herpes nucleosides has been made by the advent of 5-substituted pyrimidine nucleosides such as 5-iodo-, 5-ethyl-, 5-(2-chloroethyl)-, and (E)-5-(2-bromovinyl)- derivatives of 2'-deoxyuridine. These are highly specific inhibitors of HSV-1, HSV-2, and/or VZV infections. However, Epstein Barr virus (EBV) and HCMV are much less sensitive to these agents. In 5-substituted pyrimidine nucleosides the nature of substituents, particularly at the C-5 position, has been found to be an important determinant of anti-herpes activity. Structural requirements at the C-2 carbon of the 5

  4. Molecular mechanism by which acyclic retinoid induces nuclear localization of transglutaminase 2 in human hepatocellular carcinoma cells

    PubMed Central

    Shrestha, R; Tatsukawa, H; Shrestha, R; Ishibashi, N; Matsuura, T; Kagechika, H; Kose, S; Hitomi, K; Imamoto, N; Kojima, S

    2015-01-01

    Nuclear accumulation of transglutaminase 2 (TG2) is an important step in TG2-dependent cell death. However, the underlying molecular mechanisms for nuclear translocation of TG2 are still poorly understood. In this study, we demonstrated that acyclic retinoid (ACR) induced nuclear accumulation of TG2 in JHH-7 cells, a hepatocellular carcinoma (HCC) leading to their apoptosis. We further demonstrated molecular mechanism in nuclear-cytoplasmic trafficking of TG2 and an effect of ACR on it. We identified a novel 14-amino acid nuclear localization signal (NLS) 466AEKEETGMAMRIRV479 in the ‘C' domain and a leucine-rich nuclear export signal (NES) 657LHMGLHKL664 in the ‘D' domain that allowed TG2 to shuttle between the nuclear and cytosolic milieu. Increased nuclear import of GAPDH myc-HIS fused with the identified NLS was observed, confirming its nuclear import ability. Leptomycin B, an inhibitor of exportin-1 as well as point mutation of all leucine residues to glutamine residues in the NES of TG2 demolished its nuclear export. TG2 formed a trimeric complex with importin-α and importin-β independently from transamidase activity which strongly suggested the involvement of a NLS-based translocation of TG2 to the nucleus. ACR accelerated the formation of the trimeric complex and that may be at least in part responsible for enhanced nuclear localization of TG2 in HCC cells treated with ACR. PMID:26633708

  5. Acyclic monoterpene primary alcohol:NADP+ oxidoreductase of Rauwolfia serpentina cells: the key enzyme in biosynthesis of monoterpene alcohols.

    PubMed

    Ikeda, H; Esaki, N; Nakai, S; Hashimoto, K; Uesato, S; Soda, K; Fujita, T

    1991-02-01

    Acyclic monoterpene primary alcohol:NADP+ oxidoreductase, a key enzyme in the biosynthesis of monoterpene alcohols in plants, is unstable and has been only poorly characterized. However we have established conditions which stabilize the enzyme from Rauwolfia serpentina cells, and then purified it to homogeneity. It is a monomer with a molecular weight of about 44,000 and contains zinc ions. Various branched-chain allylic primary alcohols such as nerol, geraniol, and 10-hydroxygeraniol were substrates, but ethanol was inert. The enzyme exclusively requires NADP+ or NADPH as the cofactor. Steady-state kinetic studies showed that the nerol dehydrogenation proceeds by an ordered Bi-Bi mechanism. NADP+ binds the enzyme first and then NADPH is the second product released from it. Gas chromatography-mass spectrometric analysis of the reaction products showed that 10-hydroxygeraniol undergoes a reversible dehydrogenation to produce 10-oxogeraniol or 10-hydroxygeranial, which are oxidized further to give 10-oxogeranial, the direct precursor of iridodial. The enzyme has been found to exclusively transfer the pro-R hydrogen of NADPH to neral. The N-terminal sequence of the first 21 amino acids revealed no significant homology with those of various other proteins including the NAD(P)(+)-dependent alcohol dehydrogenases registered in a protein data bank. PMID:1864846

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

    PubMed Central

    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

  7. H4octapa-Trastuzumab: Versatile Acyclic Chelate System for 111In and 177Lu Imaging and Therapy

    PubMed Central

    Price, Eric W.; Zeglis, Brian M.; Cawthray, Jacqueline F.; Ramogida, Caterina F.; Ramos, Nicholas

    2013-01-01

    A bifunctional derivative of the versatile acyclic chelator H4octapa, p-SCNBn- H4octapa, has been synthesized for the first time. The chelator was conjugated to the HER2/neu-targeting antibody trastuzumab and labeled in high radiochemical purity and specific activity with the radioisotopes 111In and 177Lu. The in vivo behavior of the resulting radioimmunoconjugates was investigated in mice bearing ovarian cancer xenografts and compared to analogous radioimmunoconjugates employing the ubiquitous chelator DOTA. The H4octapa-trastuzumab conjugates displayed faster radiolabeling kinetics with more reproducible yields under milder conditions (15 min, RT, ~94–95%) than those based on DOTA-trastuzumab (60 min, 37 °C ~50–88%). Further, antibody integrity was better preserved in the 111In- and 177Lu-octapatrastuzumab constructs, with immunoreactive fractions of 0.99 for each compared to 0.93–0.95 for 111In- and 177Lu-DOTA-trastuzumab. These results translated to improved in vivo biodistribution profiles and SPECT imaging results for 111In- and 177Lu-octapa-trastuzumab compared to 111In- and 177Lu-DOTA-trastuzumab, with increased tumor uptake and higher tumor-to-tissue activity ratios. PMID:23901833

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

    SciTech Connect

    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.

  9. Selective Phosphorylation of South and North-Cytidine and Adenosine Methanocarba-Nucleosides by Human Nucleoside and Nucleotide Kinases Correlates with Their Growth Inhibitory Effects on Cultured Cells.

    PubMed

    Sjuvarsson, Elena; Marquez, Victor E; Eriksson, Staffan

    2015-01-01

    Here bicyclo[3.1.0]hexane locked deoxycytidine (S-MCdC, N-MCdC), and deoxyadenosine analogs (S-MCdA and N-MCdA) were examined as substrates for purified preparations of human deoxynucleoside kinases: dCK, dGK, TK2, TK1, the ribonucleoside kinase UCK2, two NMP kinases (CMPK1, TMPK) and a NDP kinase. dCK can be important for the first step of phosphorylation of S-MCdC in cells, but S-MCdCMP was not a substrate for CMPK1, TMPK, or NDPK. dCK and dGK had a preference for the S-MCdA whereas N-MCdA was not a substrate for dCK, TK1, UCK2, TK2, dGK nucleoside kinases. The cell growth experiments suggested that N-MCdC and S-MCdA could be activated in cells by cellular kinases so that a triphosphate metabolite was formed. List of abbreviations: ddC, 2', 3'-didioxycytosine, Zalcitabine; 3TC, β-L-(-)-2',3'-dideoxy-3'-thiacytidine, Lamivudine; CdA, 2-cloro-2'-deoxyadenosine, Cladribine; AraA, 9-β-D-arabinofuranosyladenine; hCNT 1-3, human Concentrative Nucleoside Transporter type 1, 2 and 3; hENT 1-4, human Equilibrative Nucleoside Transporter type 1, 2, 3, and 4. PMID:26167664

  10. The Ugi reaction in the generation of new nucleosides as potential antiviral and antileishmanial agents.

    PubMed

    Fan, Xuesen; Zhang, Xinying; Bories, Christian; Loiseau, Philippe M; Torrence, Paul F

    2007-04-01

    5-Formyl-2'-deoxyuridine-3',5'-diacetate was converted to a small library of 5-substituted pyrimidine nucleoside N-acylamino acid amides by means of a Ugi multicomponent reaction. The reaction allowed introduction of various substituents at the acyl moiety, at the amino acid alpha-amide group, and at the amino acid carboxyl function. Evaluation of these novel 5-substituted nucleosides against vaccinia virus and cowpox virus provided one compound with discernable activity against cowpox virus but five- to eightfold less active than the Cidofovir standard. More promising activity was seen for the inhibition of Leishmania donovani promastigotes. Several synthetic products showed antileishmanial activity in the 10(-5)M range. When compared to earlier studies demonstrating anti-orthopoxviral and antileishmanial activity of 5-substituted pyrimidine nucleosides, these results imply that the 5-(N-acylamino acid amide)-derivatized pyrimidine nucleosides may possess more steric bulk, greater hydrophobicity, and more flexibility than is compatible with these particular biological activities. PMID:16996561

  11. Chemical synthesis of nucleoside-gamma-[32P]triphosphates of high specific activity.

    PubMed

    Janecka, A; Panusz, H; Pankowski, J; Koziołkiewicz, W

    1980-01-01

    A simple chemical procedure for the preparation of four common ribonucleoside 5-gamma-[32P]triphosphates of high specific activity (up to 10 Ci/mmole) based on the condensation of orthophosphoric acid with the corresponding nucleoside 5-diphosphate in the presence of ethyl chloroformate as well as the methods of purification and identification of the products are described. PMID:7375446

  12. Structural and functional characterization of a noncanonical nucleoside triphosphate pyrophosphatase from Thermotoga maritima

    SciTech Connect

    Awwad, Khaldeyah; Desai, Anna; Smith, Clyde; Sommerhalter, Monika

    2013-02-01

    A 2.15 Å resolution crystal structure of TM0159 with bound IMP and enzyme-kinetic data are presented. This noncanonical nucleoside triphosphatase from T. maritima helps to maintain a correct pool of DNA and RNA precursor molecules. The hyperthermophilic bacterium Thermotoga maritima has a noncanonical nucleoside triphosphatase that catalyzes the conversion of inosine triphosphate (ITP), deoxyinosine triphosphate (dITP) and xanthosine triphosphate (XTP) into inosine monophosphate (IMP), deoxyinosine monophosphate (IMP) and xanthosine monophosphate (XMP), respectively. The k{sub cat}/K{sub m} values determined at 323 and 353 K fall between 1.31 × 10{sup 4} and 7.80 × 10{sup 4} M{sup −1} s{sup −1}. ITP and dITP are slightly preferred over XTP. Activity towards canonical nucleoside triphosphates (ATP and GTP) was not detected. The enzyme has an absolute requirement for Mg{sup 2+} as a cofactor and has a preference for alkaline conditions. A protein X-ray structure of the enzyme with bound IMP was obtained at 2.15 Å resolution. The active site houses a well conserved network of residues that are critical for substrate recognition and catalysis. The crystal structure shows a tetramer with two possible dimer interfaces. One of these interfaces strongly resembles the dimer interface that is found in the structures of other noncanonical nucleoside pyrophosphatases from human (human ITPase) and archaea (Mj0226 and PhNTPase)

  13. Carbocyclic nucleoside analogues: classification, target enzymes, mechanisms of action and synthesis

    NASA Astrophysics Data System (ADS)

    Matyugina, E. S.; Khandazhinskaya, A. P.; Kochetkov, Sergei N.

    2012-08-01

    Key biological targets (S-adenosyl-L-homocysteine hydrolase, telomerase, human immunodeficiency virus reverse transcriptase, herpes virus DNA polymerase and hepatitis B virus DNA polymerase) and the mechanisms of action of carbocyclic nucleoside analogues are considered. Structural types of analogues are discussed. Methods of synthesis for the most promising compounds and the spectrum of their biological activities are described. The bibliography includes 126 references.

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

    PubMed

    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

  15. [Synthesis, conformation, and spectroscopy of nucleoside analogues concerning their antiviral activity].

    PubMed

    Kuśmierek, Jarosław T; Stolarski, Ryszard

    2015-01-01

    Chemically modified analogues of nucleosides and nucleotides, have been thoroughly investigated since the discovery of DNA double helix by Watson and Crick in 1953 (Nature 171: 737). Chemical structures, first of all tautomerism, of the nucleic acid bases, as well as the conformations of the nucleic acids constituents, determine the secondary and tertiary structures of DNA and RNA polymers. Similarly, structural and dynamic parameters of nucleoside derivatives determine their biological activity in mutagenesis, neoplastic transformation, as well as antiviral or anticancer properties. In this review, a multidisciplinary approach of Prof. David Shugar's group is presented in the studies on nucleosides and nucleotides. It consists in chemical syntheses of suitable analogues, measurements of physicochemical and spectral parameters, conformational analysis by means of nuclear magnetic resonance (NMR) and X-ray diffraction, as well as characteristics of the nucleoside analogues as inhibitors of some selected, target enzymes, crucial in respect to antiviral activity of the analogues. These long-lasting studies follows upon the line of the main paradigm of molecular biophysics, i. e. structure-activity relationship. PMID:26677575

  16. Purification and characterization of purine nucleoside phosphorylase from developing embryos of Hyalomma dromedarii.

    PubMed

    Kamel, M Y; Fahmy, A S; Ghazy, A H; Mohamed, M A

    1991-04-01

    Purine nucleoside phosphorylase from Hyalomma dromedarii, the camel tick, was purified to apparent homogeneity. A molecular weight of 56,000 - 58,000 was estimated for both the native and denatured enzyme, suggesting that the enzyme is monomeric. Unlike purine nucleoside phosphorylase preparations from other tissues, the H. dromedarii enzyme was unstable in the presence of beta-mercaptoethanol. The enzyme had a sharp pH optimum at pH 6.5. It catalyzed the phosphorolysis and arsenolysis of ribo- and deoxyribo-nucleosides of hypoxanthine and guanine, but not of adenine or pyrimidine nucleosides. The Km values of the enzyme at the optimal pH for inosine, deoxyinosine, guanosine, and deoxyguanosine were 0.31, 0.67, 0.55, and 0.33 mM, respectively. Inactivation and kinetic studies suggested that histidine and cysteine residues were essential for activity. The pKa values determined for catalytic ionizable groups were 6-7 and 8-9. The enzyme was completely inactivated by thiol reagents and reactivated by excess beta-mercaptoethanol. The enzyme was also susceptible to pH-dependent photooxidation in the presence of methylene blue, implicating histidine. Initial velocity studies showed an intersecting pattern of double-reciprocal plots of the data, consistent with a sequential mechanism. PMID:1905141

  17. Nucleoside diphosphate kinase of Saccharomyces cerevisiae, Ynk1p: localization to the mitochondrial intermembrane space.

    PubMed Central

    Amutha, Boominathan; Pain, Debkumar

    2003-01-01

    Nucleoside diphosphate kinase (NDPK) is a highly conserved multifunctional enzyme. It catalyses the transfer of gamma phosphates from nucleoside triphosphates to nucleoside diphosphates by a mechanism that involves formation of an autophosphorylated enzyme intermediate. The phosphate is usually supplied by ATP. NDPK activity in different subcellular compartments may regulate the crucial balance between ATP and GTP or other nucleoside triphosphates. NDPKs are homo-oligomeric proteins and are predominantly localized in the cytosol. In this paper, we demonstrate that in Saccharomyces cerevisiae a small fraction of total NDPK activity encoded by YNK1 is present in the intermembrane space (IMS) of mitochondria, and the corresponding protein Ynk1p in the IMS represents approx. 0.005% of total mitochondrial proteins. Ynk1p, synthesized as a single gene product, must therefore be partitioned between cytoplasm and mitochondrial IMS fractions. A mechanism for this partitioning is suggested by our observations that interaction with a 40 kDa protein of the translocase of outer mitochondrial membrane (Tom40p), occurs preferentially with unfolded, unphosphorylated forms of Ynk1p. A population of newly translated, but not yet folded or autophosphorylated, Ynk1p intermediates may be imported into the IMS of mitochondria and trapped there by subsequent folding and oligomerization. Within the small volume of the IMS, Ynk1p may be more concentrated and may be required to supply GTP to several important proteins in this compartment. PMID:12472466

  18. Hypoxanthine enters human vascular endothelial cells (ECV 304) via the nitrobenzylthioinosine-insensitive equilibrative nucleoside transporter.

    PubMed Central

    Osses, N; Pearson, J D; Yudilevich, D L; Jarvis, S M

    1996-01-01

    The transport properties of the nucleobase hypoxanthine were examined in the human umbilical vein endothelial cell line ECV 304. Initial rates of hypoxanthine influx were independent of extracellular cations: replacement of Na+ with Li+, Rb+, N-methyl-D-glucamine or choline had no significant effect on hypoxanthine uptake by ECV 304 cells. Kinetic analysis demonstrated the presence of a single saturable system for the transport of hypoxanthine in ECV 304 cells with an apparent K(m) of 320 +/- 10 microM and a Vmax of 5.6 +/- 0.9 pmol/10(6) cells per s. Hypoxanthine uptake was inhibited by the nucleosides adenosine, uridine and thymidine (apparent Ki 41 +/- 6, 240 +/- 27 and 59 +/- 8 microM respectively) and the nucleoside transport inhibitors nitrobenzylthioinosine (NBMPR), dilazep and dipyridamole (apparent Ki 2.5 +/- 0.3, 11 +/- 3 and 0.16 +/- 0.006 microM respectively), whereas the nucleobases adenine, guanine and thymine had little effect (50% inhibition at > 1 mM). ECV 304 cells were also shown to transport adenosine via both the NBMPR-sensitive and -insensitive nucleoside carriers. Hypoxanthine specifically inhibited adenosine transport via the NBMPR-insensitive system in a competitive manner (apparent Ki 290 +/- 14 microM). These results indicate that hypoxanthine entry into ECV 304 endothelial cells is mediated by the NBMPR-insensitive nucleoside carrier present in these cells. PMID:8760371

  19. Release of nucleosides from canine and human hearts as an index of prior ischemia.

    PubMed

    Fox, A C; Reed, G E; Meilman, H; Silk, B B

    1979-01-01

    During ischemia, myocardial adenosine triphosphate is degraded to adenosine, inosine and hypoxanthine. These nucleosides are released into coronary venous blood and may provide an index of ischemia; adenosine may also participate in the autoregulation of coronary flow. In dogs, the temporal relations between reactive hyperemic flow and nucleoside concentrations in regional venous blood were correlated after brief occlusions of a segmental coronary artery. Reactive hyperemia and adenosine release peaked together in 10 seconds, persisted for 10 to 30 seconds and then decreased in a pattern consistent with the hypothesis that they are related. During initial reflow after 45 seconds of ischemia, mean concentrations of adenosine, inosine and hypoxanthine increased, respectively, to 52, 67 and 114 nmol/100 ml plasma; after 5 minutes of ischemia, the respective levels increased to 58, 1,570 and 1,134 nmol and fell quickly. In nine patients there was a similar release of nucleosides into coronary sinus blood during reperfusion after 59 to 80 minutes of ischemic arrest during cardiac surgery. With initial reflow, adenosine, inosine and hypoxanthine levels reached 65, 655 and 917 nmol/100 ml of blood, respectively. Inosine and hypoxanthine concentrations remained high for 5 to 10 minutes after cardiac beating resumed, often when production of lactate had decreased. The results indicate that postischemic release of nucleosides reaches significant levels in man as well as animals, is parallel with the duration of ischemia, is temporary and may be a useful supplement to measurement of lactate as an index of prior myocardial ischemia. PMID:758770

  20. Pseudobond parameters for QM/MM studies involving nucleosides, nucleotides, and their analogs

    NASA Astrophysics Data System (ADS)

    Chaudret, Robin; Parks, Jerry M.; Yang, Weitao

    2013-01-01

    In biological systems involving nucleosides, nucleotides, or their respective analogs, the ribose sugar moiety is the most common reaction site, for example, during DNA replication and repair. However, nucleic bases, which comprise a sizable portion of nucleotide molecules, are usually unreactive during such processes. In quantum mechanical/molecular simulations of nucleic acid reactivity, it may therefore be advantageous to describe specific ribosyl or ribosyl phosphate groups quantum mechanically and their respective nucleic bases with a molecular mechanics potential function. Here, we have extended the pseudobond approach to enable quantum mechanical/molecular mechanical simulations involving nucleotides, nucleosides, and their analogs in which the interface between the two subsystems is located between the sugar and the base, namely, the C(sp3)-N(sp2) bond. The pseudobond parameters were optimized on a training set of 10 molecules representing several nucleotide and nucleoside bases and analogs, and they were then tested on a larger test set of 20 diverse molecules. Particular emphasis was placed on providing accurate geometries and electrostatic properties, including electrostatic potential, natural bond orbital (NBO) and atoms in molecules (AIM) charges and AIM first moments. We also tested the optimized parameters on five nucleotide and nucleoside analogues of pharmaceutical relevance and a small polypeptide (triglycine). Accuracy was maintained for these systems, which highlights the generality and transferability of the pseudobond approach.