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Sample records for acyclic nucleoside phosphonate

  1. Ether lipid-ester prodrugs of acyclic nucleoside phosphonates: activity against adenovirus replication in vitro.

    PubMed

    Hartline, Caroll B; Gustin, Kortney M; Wan, William B; Ciesla, Stephanie L; Beadle, James R; Hostetler, Karl Y; Kern, Earl R

    2005-02-01

    The acyclic nucleoside phosphonate cidofovir (CDV) and its closely related analogue (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)-adenine ([S]-HPMPA) have been reported to have activity against many adenovirus (AdV) serotypes. A new series of orally active ether lipid-ester prodrugs of CDV and of (S)-HPMPA that have slight differences in the structure of their lipid esters were evaluated, in tissue-culture cells, for activity against 5 AdV serotypes. The results indicated that, against several AdV serotypes, the most active compounds were 15-2500-fold more active than the unmodified parent compounds and should be evaluated further for their potential to treat AdV infections in humans.

  2. Clinical Potential of the Acyclic Nucleoside Phosphonates Cidofovir, Adefovir, and Tenofovir in Treatment of DNA Virus and Retrovirus Infections

    PubMed Central

    De Clercq, Erik

    2003-01-01

    The acyclic nucleoside phosphonates HPMPC (cidofovir), PMEA (adefovir), and PMPA (tenofovir) have proved to be effective in vitro (cell culture systems) and in vivo (animal models and clinical studies) against a wide variety of DNA virus and retrovirus infections: cidofovir against herpesvirus (herpes simplex virus types 1 and 2 varicella-zoster virus, cytomegalovirus [CMV], Epstein-Barr virus, and human herpesviruses 6, 7, and 8), polyomavirus, papillomavirus, adenovirus, and poxvirus (variola virus, cowpox virus, vaccinia virus, molluscum contagiosum virus, and orf virus) infections; adefovir against herpesvirus, hepadnavirus (human hepatitis B virus), and retrovirus (human immunodeficiency virus types 1 [HIV-1] and 2 [HIV-2], simian immunodeficiency virus, and feline immunodeficiency virus) infections; and tenofovir against both hepadnavirus and retrovirus infections. Cidofovir (Vistide) has been officially approved for the treatment of CMV retinitis in AIDS patients, tenofovir disoproxil fumarate (Viread) has been approved for the treatment of HIV infections (i.e., AIDS), and adefovir dipivoxil (Hepsera) has been approved for the treatment of chronic hepatitis B. Nephrotoxicity is the dose-limiting side effect for cidofovir (Vistide) when used intravenously (5 mg/kg); no toxic side effects have been described for adefovir dipivoxil and tenofovir disoproxil fumarate, at the approved doses (Hepsera at 10 mg orally daily and Viread at 300 mg orally daily). PMID:14557287

  3. Estimation of apparent binding constant of complexes of selected acyclic nucleoside phosphonates with β-cyclodextrin by affinity capillary electrophoresis.

    PubMed

    Šolínová, Veronika; Mikysková, Hana; Kaiser, Martin Maxmilián; Janeba, Zlatko; Holý, Antonín; Kašička, Václav

    2016-01-01

    Affinity capillary electrophoresis (ACE) has been applied to estimation of apparent binding constant of complexes of (R,S)-enantiomers of selected acyclic nucleoside phosphonates (ANPs) with chiral selector β-cyclodextrin (βCD) in aqueous alkaline medium. The noncovalent interactions of five pairs of (R,S)-enantiomers of ANPs-based antiviral drugs and their derivatives with βCD were investigated in the background electrolyte (BGE) composed of 35 or 50 mM sodium tetraborate, pH 10.0, and containing variable concentration (0-25 mM) of βCD. The apparent binding constants of the complexes of (R,S)-enantiomers of ANPs with βCD were estimated from the dependence of effective electrophoretic mobilities of (R,S)-enantiomers of ANPs (measured simultaneously by ACE at constant reference temperature 25°C inside the capillary) on the concentration of βCD in the BGE using different nonlinear and linear calculation methodologies. Nonlinear regression analysis provided more precise and accurate values of the binding constants and a higher correlation coefficient as compared to the regression analysis of the three linearized plots of the effective mobility dependence on βCD concentration in the BGE. The complexes of (R,S)-enantiomers of ANPs with βCD have been found to be relatively weak - their apparent binding constants determined by the nonlinear regression analysis were in the range 13.3-46.4 L/mol whereas the values from the linearized plots spanned the interval 12.3-55.2 L/mol.

  4. Efficacy of the acyclic nucleoside phosphonates (S)-9-(3-fluoro-2-phosphonylmethoxypropyl)adenine (FPMPA) and 9-(2-phosphonylmethoxyethyl)adenine (PMEA) against feline immunodeficiency virus.

    PubMed

    Hartmann, K; Kuffer, M; Balzarini, J; Naesens, L; Goldberg, M; Erfle, V; Goebel, F D; De Clercq, E; Jindrich, J; Holy, A; Bischofberger, N; Kraft, W

    1998-02-01

    The acyclic nucleoside phosphonates (S)-9-(3-fluoro-2-phosphonylmethoxypropyl)adenine (FPMPA) and 9-(2-phosphonylmethoxyethyl)adenine (PMEA) were evaluated for their efficacy and side effects in a double-blind placebo-controlled trial using naturally occurring feline immunodeficiency virus (FIV)-infected cats. This natural retrovirus animal model is considered highly relevant for the pathogenesis and chemotherapy of HIV in humans. Both PMEA and FPMPA proved effective in ameliorating the clinical symptoms of FIV-infected cats, as measured by several clinical parameters including the incidence and severity of stomatitis, Karnofsky's score, immunologic parameters such as relative and absolute CD4+ lymphocyte counts, and virologic parameters including proviral DNA levels in peripheral blood mononuclear cells (PBMC) of drug-treated animals. In contrast with PMEA, FPMPA showed no hematologic side effects at a dose that was 2.5-fold higher than PMEA.

  5. Evaluation of novel acyclic nucleoside phosphonates against human and animal gammaherpesviruses revealed an altered metabolism of cyclic prodrugs upon Epstein-Barr virus reactivation in P3HR-1 cells.

    PubMed

    Coen, Natacha; Duraffour, Sophie; Naesens, Lieve; Krecmerová, Marcela; Van den Oord, Joost; Snoeck, Robert; Andrei, Graciela

    2013-11-01

    Acyclic nucleoside phosphonates (ANPs), such as (S)-1-[(3-hydroxy-2-phosphonomethoxy)propyl)]cytosine (HPMPC), are an important group of broad-spectrum antiviral agents with activity against DNA viruses. In this report, we present the in vitro potencies of novel ANPs against gammaherpesviruses, including Kaposi's sarcoma-associated herpesvirus, Epstein-Barr virus (EBV), and three animal gammaherpesviruses. 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine (HPMP-5-azaC), (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]-3-deazaadenine (3-deaza-HPMPA), and their cyclic derivatives have emerged as highly potent antigammaherpesvirus agents. Interestingly, cyclic prodrugs of ANPs exhibited reduced activities against EBV strain P3HR-1, but not against EBV strain Akata. Cell culture metabolism studies with HPMPC and cyclic HPMPC revealed that these differences were attributable to an altered drug metabolism in P3HR-1 cells after EBV reactivation and, more specifically, to a reduced hydrolysis of cyclic HPMPC by cyclic CMP phosphodiesterase. We did not correlate this effect with phosphodiesterase downregulation, or to functional mutations. Instead, altered cyclic AMP levels in P3HR-1 cells indicated a competitive inhibition of the phosphodiesterase by this cyclic nucleotide. Finally, both HPMPC and HPMP-5-azaC emerged as highly effective inhibitors in vivo through significant inhibition of murine gammaherpesvirus replication and dissemination. With the current need for potent antigammaherpesvirus agents, our findings underline the requirement of appropriate surrogate viruses for antiviral susceptibility testing and highlight HPMP-5-azaC as a promising compound for future clinical development.

  6. Synthesis of some novel hydrazono acyclic nucleoside analogues

    PubMed Central

    Khalafi-Nezhad, Ali; Behrouz, Somayeh

    2010-01-01

    Summary The syntheses of novel hydrazono acyclic nucleosides similar to miconazole scaffolds are described. In this series of acyclic nucleosides, pyrimidine as well as purine and other azole derivatives replaced the imidazole function in miconazole and the ether group was replaced with a hydrazone moiety using phenylhydrazine. To interpret the dominant formation of (E)-hydrazone derivatives rather than (Z)-isomers, PM3 semiempirical quantum mechanic calculations were carried out which indicated that the (E)-isomers had the lower heats of formation. PMID:20563270

  7. 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.

  8. Anti-HIV Nucleoside Phosphonate GS-9148 and Its Prodrug GS-9131: Scale Up of a 2'-F Modified Cyclic Nucleoside Phosphonate and Synthesis of Selected Amidate Prodrugs.

    PubMed

    Mackman, Richard L

    2014-03-26

    Nucleoside phosphonate analogs are an important class of antiviral drugs for the treatment of HIV and HBV. The most recent nucleoside phosphonate to progress to clinical development is GS-9131, a cyclic nucleoside phosphonate (CNP). This unit contains procedures for the synthesis of the parent CNP 2'-Fd4AP (GS-9148) and selected monoamidate and bisamidate prodrugs, including the monoamidate clinical prodrug GS-9131. The first basic protocol of this unit details improved procedures for the preparation of 2'-Fd4AP and related phosphonate esters by introduction of a hydroxylmethyl phosphonate ester regioselectively and stereoselectively onto a furanose core via a glycal intermediate. The method described is believed to be robust and flexible, allowing for a variety of analogs with other nucleobases or furanose 2'-ring substitutions to be prepared. The preparation of monoamidate and bisamidate prodrugs either on the phosphonate diacid or its monophenyl ester is then described in the second and third basic protocols of this unit.

  9. 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

  10. One-pot synthesis of acyclic nucleosides from carbohydrate derivatives, by combination of tandem and sequential reactions.

    PubMed

    Boto, Alicia; Hernández, Dácil; Hernández, Rosendo; Alvarez, Eleuterio

    2007-12-07

    The design of processes which combine tandem and sequential reactions allows the transformation of readily available precursors into high-profit products. This strategy is illustrated by the one-pot synthesis of acyclic nucleosides, which are potential antiviral compounds, from readily available carbohydrates. The reaction conditions are mild, compatible with most functional groups. Depending on the starting sugar, both common and uncommon acyclic chains can be prepared. These polyhydroxylated chains can be combined with different bases to generate diversity.

  11. 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).

  12. Acyclic phosphonate nucleotides and human adenylate kinases: impact of a borano group on alpha-P position.

    PubMed

    Topalis, D; Alvarez, K; Barral, K; Munier-Lehmann, H; Schneider, B; Véron, M; Guerreiro, C; Mulard, L; El-Amri, C; Canard, B; Deville-Bonne, D

    2008-04-01

    Adenylate kinases are involved in the activation of antiviral drugs such as the acyclic phosphonates analogs PMEA and (R)PMPA. We examine the in vitro phosphorylation of PMEA and PMPA bearing a borano- or a H- group on the phosphorus atom. The alpha-borano or alpha-H on PMEA and PMPA were detrimental to the activity of recombinant human AMP kinases 1 and 2. Docking PMEA to the active site of AMP kinase 1 indicated that the borano group may prevent two conserved critical Arg interactions with the alpha-phosphate, resulting in substrate bad positioning.

  13. Solution-phase parallel synthesis of acyclic nucleoside libraries of purine, pyrimidine, and triazole acetamides.

    PubMed

    Pathak, Ashish K; Pathak, Vibha; Reynolds, Robert C

    2014-09-08

    Molecular diversity plays a pivotal role in modern drug discovery against phenotypic or enzyme-based targets using high throughput screening technology. Under the auspices of the Pilot Scale Library Program of the NIH Roadmap Initiative, we produced and report herein a diverse library of 181 purine, pyrimidine, and 1,2,4-triazole-N-acetamide analogues which were prepared in a parallel high throughput solution-phase reaction format. A set of assorted amines were reacted with several nucleic acid N-acetic acids utilizing HATU as the coupling reagent to produce diverse acyclic nucleoside N-acetamide analogues. These reactions were performed using 24 well reaction blocks and an automatic reagent-dispensing platform under inert atmosphere. The targeted compounds were purified on an automated purification system using solid sample loading prepacked cartridges and prepacked silica gel columns. All compounds were characterized by NMR and HRMS, and were analyzed for purity by HPLC before submission to the Molecular Libraries Small Molecule Repository (MLSMR) at NIH. Initial screening through the Molecular Libraries Probe Production Centers Network (MLPCN) program, indicates that several analogues showed diverse and interesting biological activities.

  14. Design, synthesis and evaluation of a series of acyclic fleximer nucleoside analogues with anti-coronavirus activity.

    PubMed

    Peters, Hannah L; Jochmans, Dirk; de Wilde, Adriaan H; Posthuma, Clara C; Snijder, Eric J; Neyts, Johan; Seley-Radtke, Katherine L

    2015-08-01

    A series of doubly flexible nucleoside analogues were designed based on the acyclic sugar scaffold of acyclovir and the flex-base moiety found in the fleximers. The target compounds were evaluated for their antiviral potential and found to inhibit several coronaviruses. Significantly, compound 2 displayed selective antiviral activity (CC50 >3× EC50) towards human coronavirus (HCoV)-NL63 and Middle East respiratory syndrome-coronavirus, but not severe acute respiratory syndrome-coronavirus. In the case of HCoV-NL63 the activity was highly promising with an EC50 <10 μM and a CC50 >100 μM. As such, these doubly flexible nucleoside analogues are viewed as a novel new class of drug candidates with potential for potent inhibition of coronaviruses.

  15. Synthesis of antisense oligonucleotides containing acyclic alkynyl nucleoside analogs and their biophysical and biological properties.

    PubMed

    Ogata, Aya; Maeda, Yusuke; Ueno, Yoshihito

    2017-04-01

    The synthesis of oligonucleotide (ON) analogs, which can be used as antisense molecules, has recently gained much attention. Here, we report the synthesis and properties of an ON analog containing acyclic thymidine and cytidine analogs with a 4-pentyl-1,2-diol instead of the d-ribofuranose moiety. The incorporation of these analogs into the ON improved its nuclease resistance to 3'-exonucleases. Furthermore, it was found that the incorporation of the acyclic thymidine analog into a DNA/RNA duplex accelerates the RNA cleavage of a DNA/RNA duplex by Escherichia coli RNase H.

  16. Revaluation of biomass-derived furfuryl alcohol derivatives for the synthesis of carbocyclic nucleoside phosphonate analogues

    PubMed Central

    Sidi Mohamed, Bemba; Périgaud, Christian

    2017-01-01

    The racemic synthesis of new carbocyclic nucleoside methylphosphonate analogues bearing purine bases (adenine and guanine) was accomplished using bio-sourced furfuryl alcohol derivatives. All compounds were prepared using a Mitsunobu coupling between the heterocyclic base and an appropriate carbocyclic precursor. After deprotection, the compounds were evaluated for their activity against a large number of viruses. However, none of them showed significant antiviral activity or cytotoxicity. PMID:28326134

  17. Revaluation of biomass-derived furfuryl alcohol derivatives for the synthesis of carbocyclic nucleoside phosphonate analogues.

    PubMed

    Sidi Mohamed, Bemba; Périgaud, Christian; Mathé, Christophe

    2017-01-01

    The racemic synthesis of new carbocyclic nucleoside methylphosphonate analogues bearing purine bases (adenine and guanine) was accomplished using bio-sourced furfuryl alcohol derivatives. All compounds were prepared using a Mitsunobu coupling between the heterocyclic base and an appropriate carbocyclic precursor. After deprotection, the compounds were evaluated for their activity against a large number of viruses. However, none of them showed significant antiviral activity or cytotoxicity.

  18. Analogues of acyclic nucleosides derived from tris-(hydroxymethyl)phosphine oxide or bis-(hydroxymethyl)phosphinic acid coupled to DNA nucleobases.

    PubMed

    Nawrot, Barbara; Michalak, Olga; De Clercq, Erik; Stec, Wojciech J

    2004-11-01

    A series of novel acyclic nucleoside analogues containing bis-(hydroxymethyl)phosphinic acid (BHPA) or tris(hydroxymethyl)phosphine oxide (THPO) coupled with DNA nucleobases or with 5-fluorouracil were prepared and their antiviral activity was studied against cytomegalovirus (CMV), varicella-zoster virus (VZV), parainfluenza-virus type 3, reovirus-type 1, sindbis, coxsackie B4, punta toro, vesicular stomatitis and respiratory syncytial virus, herpes simplex virus-type 1 (KOS) and type 2 (G), vaccinia virus and herpes simplex virus-1 (TK- KOS ACVr). No specific antiviral effects were noted for any of test compounds against viruses evaluated, except thymine, cytosine and adenine derivatives of BHPA exerting borderline activity against respiratory syncytial virus at the 80 mg/ml concentration.

  19. Mechanism of inhibition of adenovirus DNA replication by the acyclic nucleoside triphosphate analogue (S)-HPMPApp: influence of the adenovirus DNA binding protein.

    PubMed Central

    Mul, Y M; van Miltenburg, R T; De Clercq, E; van der Vliet, P C

    1989-01-01

    The acyclic adenosine analogue (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [S]-HPMPA) is a potent and selective inhibitor of adenovirus (Ad) replication in cell culture. We studied the mechanism of inhibition using a reconstituted in vitro DNA replication system. The diphosphoryl derivative (S)-HPMPApp, but not (S)-HPMPA, inhibited the DNA replication of origin containing fragments strongly. The inhibitory effect was exerted at the level of elongation, while initiation was resistant to the drug. Remarkably, the elongation of short strands was only slightly impaired, while inhibition was maximal upon synthesis of long DNA fragments. (S)-HPMPApp appeared to be competitive with dATP, suggesting that the Ad DNA polymerase is the prime target for the drug. We purified the Ad DNA polymerase in complex to the precursor terminal protein to homogeneity from cells infected with overproducing recombinant vaccinia viruses. Employing gapped DNA or poly(dT).oligo(dA) templates, only a weak inhibition was observed. However, inhibition was strongly enhanced in the presence of the adenovirus DNA binding protein (DBP). We interpret this to mean that the increased processivity of the polymerization reaction in the presence of DBP leads to increased drug sensitivity. Images PMID:2587248

  20. 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.

  1. Analysis of acyclic nucleoside modifications in siRNAs finds sensitivity at position 1 that is restored by 5′-terminal phosphorylation both in vitro and in vivo

    PubMed Central

    Kenski, Denise M.; Cooper, Abby J.; Li, Jenny J.; Willingham, Aarron T.; Haringsma, Henry J.; Young, Tracy A.; Kuklin, Nelly A.; Jones, Jeffrey J.; Cancilla, Mark T.; McMasters, Daniel R.; Mathur, Melina; Sachs, Alan B.; Flanagan, W. Michael

    2010-01-01

    Small interfering RNAs (siRNAs) are short, double-stranded RNAs that use the endogenous RNAi pathway to mediate gene silencing. Phosphorylation facilitates loading of a siRNA into the Ago2 complex and subsequent cleavage of the target mRNA. In this study, 2′, 3′ seco nucleoside modifications, which contain an acylic ribose ring and are commonly called unlocked nucleic acids (UNAs), were evaluated at all positions along the guide strand of a siRNA targeting apolipoprotein B (ApoB). UNA modifications at positions 1, 2 and 3 were detrimental to siRNA activity. UNAs at positions 1 and 2 prevented phosphorylation by Clp1 kinase, abrogated binding to Ago2, and impaired Ago2-mediated cleavage of the mRNA target. The addition of a 5′-terminal phosphate to siRNA containing a position 1 UNA restored ApoB mRNA silencing, Ago2 binding, and Ago2 mediated cleavage activity. Position 1 UNA modified siRNA containing a 5′-terminal phosphate exhibited a partial restoration of siRNA silencing activity in vivo. These data reveal the complexity of interpreting the effects of chemical modification on siRNA activity, and exemplify the importance of using multiple biochemical, cell-based and in vivo assays to rationally design chemically modified siRNA destined for therapeutic use. PMID:19917641

  2. Gas recirculator for acyclic machines

    NASA Astrophysics Data System (ADS)

    Balsa, T. F.

    1985-05-01

    The present invention relates to acyclic machines of the type using liquid metal collectors, and more particularly to an improvement for retaining the liquid metal in such machines. Radial type acyclic motors and generators generally include a metallic disk rotor rotating on a shaft between electromagnetic stator poles excited by field coils wound concentric with the shaft. Instead of solid brush, current collectors at the rotor periphery, liquid metal collectors are sometimes used to close the electrical current loop between the shaft and the rotor, and an inert pressurized cover gas fills the gaps between the rotating components and the stationary housing. A cover has recirculator in an acyclic generator having liquid metal collectors for reducing entrainment of the liquid metal in the gas. Radial passages in the stator housing provide natural recirculating paths for the cover gas to flow radially outward along the sides of the rotor and return inwardly through the passages. Scoops or lips located inward of the liquid metal collector divert the outward gas flow into the passages to minimize contact of the gas with the liquid metal.

  3. Metabolic properties of phosphonate esters.

    PubMed

    Somogyi, G; Buchwald, P; Bodor, N

    2004-05-01

    The object of the present work was to investigate the difference in the metabolism of the phosphonate derivatives of primary or secondary hydroxyl groups. To study the phosphorolytic cleavage of such P-O bonds, zidovudine (AZT) hexanoyloxymethyl-methylphosphonate (HOM-AZT-P), an ester of a primary OH functionality, and methyl-pivaloyloxymethyl-testosterylphosphonate (POM-T-P), an ester of a secondary OH functionality, were prepared. The actions of pure enzymes such as alkaline phosphatase and phosphodiesterase on the corresponding phosphonate compounds (AZT-P and T-P) were investigated at various pH values. The phosphonate derivative of the secondary hydroxyl group of testosterone proved completely resistant to such phosphorolytic attacks, and release of free testosterone could not be detected. The phosphonate derivative of the primary hydroxyl group of zidovudine proved resistant to phosphodiesterase, but not to alkaline phosphatase, and in this second case, release of free zidovudine could be detected.

  4. 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.

  5. Phosphonate utilization by bacteria.

    PubMed Central

    Cook, A M; Daughton, C G; Alexander, M

    1978-01-01

    Bacteria able to use at least one of 13 ionic alkylphosphonates of O-alkyl or O,O-dialkyl alkylphosphonates as phosphorus sources were isolated from sewage and soil. Four of these isolates used 2-aminoethylphosphonic acid (AEP) as a sole carbon, nitrogen, and phosphorus source. None of the other phosphonates served as a carbon source for the organisms. One isolate, identified as Pseudomonas putida, grew with AEP as its sole carbon, nitrogen, and phosphorus source and released nearly all of the organic phosphorus as orthophosphate and 72% of the AEP nitrogen as ammonium. This is the first demonstration of utilization of a phosphonoalkyl moiety as a sole carbon source. Cell-free extracts of P. putida contained an inducible enzyme system that required pyruvate and pyridoxal phosphate to release orthophosphate from AEP; acetaldehyde was tentatively identified as a second product. Phosphite inhibited the enzyme system. PMID:618850

  6. 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.

  7. 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

  8. 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

  9. Acyclic telluroiminium salts: isolation and characterization.

    PubMed

    Mutoh, Yuichiro; Murai, Toshiaki; Yamago, Shigeru

    2004-12-29

    The isolation, structure, and reactions of acyclic telluroiminium salts were disclosed. The delocalization of electrons on the tellurium atom and the partial double-bond character of C-Te bonds in the salts are discussed on the basis of X-ray molecular structure analysis, 13C and 125Te NMR spectroscopy, and molecular orbital calculation.

  10. Refactoring Problem of Acyclic Extended Free-Choice Workflow Nets to Acyclic Well-Structured Workflow Nets

    NASA Astrophysics Data System (ADS)

    Yamaguchi, Shingo

    A workflow net (WF-net for short) is a Petri net which represents a workflow. There are two important subclasses of WF-nets: extended free-choice (EFC for short) and well-structured (WS for short). It is known that most actual workflows can be modeled as EFC WF-nets; Acyclic WS is a subclass of acyclic EFC but has more analysis methods. An acyclic EFC WF-net may be transformed to an acyclic WS WF-net without changing the external behavior of the net. We name such a transformation Acyclic EFC WF-net refactoring. We give a formal definition of acyclic EFC WF-net refactoring problem. We also give a necessary condition and a sufficient condition for solving the problem. Those conditions can be checked in polynomial time. These result in the enhancement of the analysis power of acyclic EFC WF-nets.

  11. 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...

  12. Genetics Home Reference: purine nucleoside phosphorylase deficiency

    MedlinePlus

    ... patients with purine nucleoside phosphorylase deficiency. Nucleosides Nucleotides Nucleic Acids. 2004 Oct;23(8-9):1411-5. Erratum in: Nucleosides Nucleotides Nucleic Acids. 2005;24(4):303. Citation on PubMed Nyhan ...

  13. Phosphonated chelates for nuclear imaging.

    PubMed

    Abada, Sabah; Lecointre, Alexandre; Christine, Câline; Ehret-Sabatier, Laurence; Saupe, Falk; Orend, Gertraud; Brasse, David; Ouadi, Ali; Hussenet, Thomas; Laquerrière, Patrice; Elhabiri, Mourad; Charbonnière, Loïc J

    2014-12-21

    A series of bis-, tris- and tetra-phosphonated pyridine ligands is presented. In view of their potential use as chelates for radiopharmaceutical applications, the physico-chemical properties of the ligands and of their Co(II), Ni(II), Cu(II), and Zn(II) complexes were studied by means of potentiometry and UV-Vis absorption spectroscopy. The pKa values of the ligands and of the complexes, as well as the stability constants for the formation of the complexes, are presented. The kinetic aspects of the formation of Cu(II) complexes and of their dissociation in acidic media were studied by means of stopped flow experiments, and the stability of the Cu(II) complex toward reduction to Cu(I) was investigated by cyclic voltammetry and by titration with different reducing agents. The different thermodynamic and kinetic aspects of the polyphosphonated ligands were compared with regard to the impact of the number of phosphonic acid functions. Considering the very promising properties for complexation, preliminary SPECT/CT imaging experiments were carried out on mice with (99m)Tc using the bis- and tetra-phosphonated ligands L(2) and L(1). Finally, a bifunctional version of chelate L(1), L*, was used to label MTn12, a rat monoclonal antibody with both specificity and relatively high affinity for murine tenascin-C. The labeling was monitored by MALDI/MS spectrometry and the affinity of the labeled antibody was checked by immunostaining experiments. After chelation with (99m)Tc, the (99m)Tc-L*-MTn12 antibody was injected into a transgenic mouse with breast cancer and the biodistribution of the labeled antibody was followed by SPECT/CT imaging.

  14. A plausibly prebiotic synthesis of phosphonic acids.

    PubMed

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

    1995-11-30

    The insolubility of calcium phosphate in water is a significant stumbling block in the chemistry required for the origin of life. The discovery of alkyl phosphonic acids in the Murchison meteorite suggests the possibility of delivery of these water-soluble, phosphorus-containing molecules by meteorites or comets to the early Earth. This could have provided a supply of organic phosphorus for the earliest stages of chemical evolution; although probably not components of early genetic systems, phosphonic acids may have been precursors to the first nucleic acids. Here we report the synthesis of several phosphonic acids, including the most abundant found in the Murchison meteorite, by ultraviolet irradiation of orthophosphorous acid in the presence of formaldehyde, primary alcohols, or acetone. We argue that similar reactions might explain the presence of phosphonic acids in Murchison, and could also have occurred on the prebiotic Earth.

  15. Acyclic archaebacterial ether lipids in swamp sediments

    NASA Astrophysics Data System (ADS)

    Pauly, George G.; Van Vleet, Edward S.

    1986-06-01

    Acyclic phytanyl diether glycerol and biphytanyl ether lipids have been quantified in two modern swamp sediment cores in concentrations ranging up to 360 μg/ml porewater. Methanogenic bacteria are the only known source organisms which can inhabit the swamp sediments. Variations in relative abundance between these lipids may reflect taxonomic changes in methanogen populations or the stage of growth. Maxima in methanogen lipid concentrations coincide with local maxima of 13C of organic matter, possibly the result of a pool effect on CO 2 or acetate. Methane production estimates calculated from lipid concentrations in swamp sediments range from 0.1 to 1.3 mmol cm -2 yr -1, values which are consistent with published methane fluxes.

  16. Community detection in directed acyclic graphs

    NASA Astrophysics Data System (ADS)

    Speidel, Leo; Takaguchi, Taro; Masuda, Naoki

    2015-08-01

    Some temporal networks, most notably citation networks, are naturally represented as directed acyclic graphs (DAGs). To detect communities in DAGs, we propose a modularity for DAGs by defining an appropriate null model (i.e., randomized network) respecting the order of nodes. We implement a spectral method to approximately maximize the proposed modularity measure and test the method on citation networks and other DAGs. We find that the attained values of the modularity for DAGs are similar for partitions that we obtain by maximizing the proposed modularity (designed for DAGs), the modularity for undirected networks and that for general directed networks. In other words, if we neglect the order imposed on nodes (and the direction of links) in a given DAG and maximize the conventional modularity measure, the obtained partition is close to the optimal one in the sense of the modularity for DAGs. Contribution to the Topical Issue "Temporal Network Theory and Applications", edited by Petter Holme.

  17. 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.

  18. 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

  19. Determination of acid-base dissociation constants of amino- and guanidinopurine nucleotide analogs and related compounds by capillary zone electrophoresis.

    PubMed

    Solínová, Veronika; Kasicka, Václav; Koval, Dusan; Cesnek, Michal; Holý, Antonín

    2006-03-01

    CZE has been applied for determination of acid-base dissociation constants (pKa) of ionogenic groups of newly synthesized amino- and (amino)guanidinopurine nucleotide analogs, such as acyclic nucleoside phosphonate, acyclic nucleoside phosphonate diesters and other related compounds. These compounds bear characteristic pharmacophores contained in various important biologically active substances, such as cytostatics and antivirals. The pKa values of ionogenic groups of the above compounds were determined by nonlinear regression analysis of the experimentally measured pH dependence of their effective electrophoretic mobilities. The effective mobilities were measured by CZE performed in series of BGEs in a broad pH range (3.50-11.25), at constant ionic strength (25 mM) and temperature (25 degrees C). pKa values were determined for the protonated guanidinyl group in (amino)guanidino 9-alkylpurines and in (amino)guanidinopurine nucleotide analogs, such as acyclic nucleoside phosphonates and acyclic nucleoside phosphonate diesters, for phosphonic acid to the second dissociation degree (-2) in acyclic nucleoside phosphonates of amino and (amino)guanidino 9-alkylpurines, and for protonated nitrogen in position 1 (N1) of purine moiety in acyclic nucleoside phosphonates of amino 9-alkylpurines. Thermodynamic pKa of protonated guanidinyl group was estimated to be in the range of 7.75-10.32, pKa of phosphonic acid to the second dissociation degree achieved values of 6.64-7.46, and pKa of protonated nitrogen in position 1 of purine was in the range of 4.13-4.89, depending on the structure of the analyzed compounds.

  20. Chiral hydroxy phosphonates: synthesis, configuration and biological properties

    NASA Astrophysics Data System (ADS)

    Kolodiazhnyi, Oleg I.

    2006-03-01

    Published data on the synthesis, absolute configurations and biological properties of chiral hydroxy phosphonates are generalised and described systematically. Examples of asymmetric synthesis of hydroxy phosphonates by the phospho-aldol reaction, reduction of keto phosphonates, chemo-enzymatic approach, and so on are discussed. Methods for determination of the optical purity and absolute configuration of hydroxy phosphonates using modification by chiral reagents, NMR, circular dichroism, GLC and HPLC on columns with chiral sorbents are considered. The significance of hydroxy phosphonates as promising compounds for the development of new drugs and bioregulators is demonstrated.

  1. Synthesis of substituted mono- and diindole C-nucleoside analogues from sugar terminal alkynes by sequential sonogashira/heteroannulation reaction.

    PubMed

    Zhang, Fuyi; Mu, Delong; Wang, Liming; Du, Pengfei; Han, Fen; Zhao, Yufen

    2014-10-17

    The synthesis of substituted mono- and diindole C-nucleoside analogues has been achieved in good to excellent yields by sequential Sonogashira coupling/NaAuCl4-catalyzed heteroannulation reactions of substituted 2-iodoanilines with various sugar terminal alkynes in one pot. The method is general, mild, and efficient and suitable for a wide range of sugar substrates, and 42 examples are given. The amino group of the substituted 2-iodoanilines is unprotected. The sugar terminal alkynes include furanosides, pyranosides, and acyclic glycosides with free hydroxyl groups, sensitive functional subtituents, and various protecting groups having different steric hindrance.

  2. Acyclic Tethers Mimicking Subunits of Polysaccharide Ligands: Selectin Antagonists

    PubMed Central

    2014-01-01

    We report on the design and synthesis of molecules having E- and P-selectins blocking activity both in vitro and in vivo. The GlcNAc component of the selectin ligand sialyl LewisX was replaced by an acyclic tether that links two saccharide units. The minimization of intramolecular dipole–dipole interactions and the gauche effect would be at the origin of the conformational bias imposed by this acyclic tether. The stereoselective synthesis of these molecules, their biochemical and biological evaluations using surface plasmon resonance spectroscopy (SPR), and in vivo assays are described. Because the structure of our analogues differs from the most potent E-selectin antagonists reported, our acyclic analogues offer new opportunities for chemical diversity. PMID:25221666

  3. [Application of directed acyclic graphs in control of confounding].

    PubMed

    Xiang, R; Dai, W J; Xiong, Y; Wu, X; Yang, Y F; Wang, L; Dai, Z H; Li, J; Liu, A Z

    2016-07-01

    Observational study is a method most commonly used in the etiology study of epidemiology, but confounders, always distort the true causality between exposure and outcome when local inferencing. In order to eliminate these confounding, the determining of variables which need to be adjusted become a key issue. Directed acyclic graph(DAG)could visualize complex causality, provide a simple and intuitive way to identify the confounding, and convert it into the finding of the minimal sufficient adjustment for the control of confounding. On the one hand, directed acyclic graph can choose less variables, which increase statistical efficiency of the analysis. On the other hand, it could help avoiding variables that is not measured or with missing values. In a word, the directed acyclic graph could facilitate the reveal of the real causality effectively.

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

    NASA Astrophysics Data System (ADS)

    Gel'man, Boris D.

    2010-12-01

    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.

  5. The chemistry of nicotinamide adenine dinucleotide (NAD) analogues containing C-nucleosides related to nicotinamide riboside.

    PubMed

    Pankiewicz, Krzysztof W; Watanabe, Kyoichi A; Lesiak-Watanabe, Krystyna; Goldstein, Barry M; Jayaram, Hiremagalur N

    2002-04-01

    Oncolytic C-nucleosides, tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide) and benzamide riboside (3-beta-D-ribofuranosylbenzamide) are converted in cell into active metabolites thiazole-4-carboxamide- and benzamide adenine dinucleotide, TAD and BAD, respectively. TAD and BAD as NAD analogues were found to bind at the nicotinamide adenine dinucleotide (cofactor NAD) site of inosine monophosphate dehydrogenase (IMPDH), an important target in cancer treatment. The synthesis and evaluation of anticancer activity of a number of C-nucleosides related to tiazofurin and nicotinamide riboside then followed and are reviewed herein. Interestingly, pyridine C-nucleosides (such as C-nicotinamide riboside) are not metabolized into the corresponding NAD analogues in cell. Their conversion by chemical methods is described. As dinucleotides these compounds show inhibition of IMPDH in low micromolar level. Also, the synthesis of BAD in metabolically stable bis(phosphonate) form is discussed indicating the usefulness of such preformed inhibitors in drug development. Among tiazofurin analogues, Franchetti and Grifantini found, that the replacement of the sulfur by oxygen (as in oxazafurin) but not the removal of nitrogen (tiophenfurin) of the thiazole ring resulted in inactive compounds. The anti cancer activity of their synthetic dinucleotide analogues indicate that inactive compounds are not only poorly metabolized in cell but also are weak inhibitors of IMPDH as dinucleotides.

  6. 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...

  7. 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...

  8. 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...

  9. 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...

  10. 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...

  11. Acyclic glycosidopyrroles analogues of ganciclovir: synthesis and biological activity.

    PubMed

    Diana, P; Barraja, P; Almerico, A M; Dattolo, G; Mingoia, F; Loi, A G; Congeddu, E; Musiu, C; Putzolu, M; La Colla, P

    1997-05-01

    Acyclic glycosidopyrroles of type 3 were synthetized in good overall yields, according to the Scheme. When evaluated for antiviral activity against DNA and RNA viruses, only compound in which R1 = R2 = Ph, R3 = NH2 was found to inhibit the HIV-1 replication at concentrations that were not cytotoxic for MT-4 cells.

  12. 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.

  13. 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.

  14. Base-modified nucleosides: etheno derivatives

    NASA Astrophysics Data System (ADS)

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

    2016-04-01

    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..

  15. 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

  16. Marine nucleosides: structure, bioactivity, synthesis and biosynthesis.

    PubMed

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

    2014-12-02

    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.

  17. 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...

  18. 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...

  19. 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...

  20. 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...

  1. 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...

  2. 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...

  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 721.10677 - Alkyl phosphonate (generic).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... CONTROL ACT SIGNIFICANT NEW USES OF CHEMICAL SUBSTANCES Significant New Uses for Specific Chemical Substances § 721.10677 Alkyl phosphonate (generic). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified generically as alkyl phosphonate (PMN...

  5. Methoxymethyl (MOM) group nitrogen protection of pyrimidines bearing C-6 acyclic side-chains.

    PubMed

    Kraljević, Tatjana Gazivoda; Petrović, Martina; Krištafor, Svjetlana; Makuc, Damjan; Plavec, Janez; Ross, Tobias L; Ametamey, Simon M; Raić-Malić, Silvana

    2011-06-20

    Novel N-methoxymethylated (MOM) pyrimidine (4-13) and pyrimidine-2,4-diones (15-17) nucleoside mimetics in which an isobutyl side-chain is attached at the C-6 position of the pyrimidine moiety were synthesized. Synthetic methods via O-persilylated or N-anionic uracil derivatives have been evaluated for the synthesis of N-1- and/or N-3-MOM pyrimidine derivatives with C-6 acyclic side-chains. A synthetic approach using an activated N-anionic pyrimidine derivative afforded the desired N,N-1,3-diMOM and N-1-MOM pyrimidines 4 and 5 in good yield. Introduction of fluorine into the side-chain was performed with DAST as the fluorinating reagent to give a N,N-1,3-diMOM pyrimidine 13 with a 1-fluoro-3-hydroxyisobutyl moiety at C-6. Conformational study of the monotritylated N-1-MOM pyrimidine 12 by the use of the NOE experiments revealed the predominant conformation of the compound to be one where the hydroxymethyl group in the C-6 side-chain is close to the N-1-MOM moiety, while the OMTr is in proximity to the CH(3)-5 group. Contrary to this no NOE enhancements between the N-1-MOM group and hydroxymethyl or fluoromethyl protons in 13 were observed, which suggested a nonrestricted rotation along the C-6 side-chain. Fluorinated N,N-1,3-diMOM pyrimidine 13 emerged as a model compound for development of tracer molecules for non-invasive imaging of gene expression using positron emission tomography (PET).

  6. Hydrophosphorylation of substituted alkynes by phosphonic acids

    SciTech Connect

    Nifant'ev, E.F.; Solovetskaya, L.A.; Maslennikova, V.I.; Sergeev, N.M.

    1987-08-20

    Hydrophosphorylation of functionally substituted alkynes by phosphonic acids can be a convenient method for synthesis of functionally substituted mono- and diphosphine oxides. The ease of hydrophosphorylation is determined by the strength of the negative inductive effect of the substituents on the triple bond and the steric factor. The structure of the bis-adducts was confirmed by elementary analysis and the /sup 31/P and /sup 13/C NMR spectra. The /sup 31/P NMR spectrum is an AB two-spin system. The values of the chemical shifts and spin-spin interaction constants /sup 3/J/sub PP/ are in agreement with the data in the literature for similar compounds.

  7. Reaction of perfluoroalkyl grignard reagents with phosphorus trihalides: a new route to perfluoroalkyl-phosphonous and -phosphonic acids.

    PubMed

    Hosein, Adil I; Le Goff, Xavier F; Ricard, Louis; Caffyn, Andrew J M

    2011-02-21

    The reaction of perfluoroalkyl Grignard reagents with phosphorus(III) halides was explored. In the process a new convenient, one-pot, high yield method for the synthesis of (perfluoroalkyl)phosphonic acids has been developed. Perfluoroalkyl Grignard reagents react with phosphorus trichloride or phosphorus tribromide to form (perfluoroalkyl)phosphonous dihalides. Hydrolysis gives the corresponding (perfluoroalkyl)phosphonous acids. Oxidation of the phosphonous acids with H(2)O(2) produces (perfluoroalkyl)phosphonic acids in 60-78% overall yields, based on the corresponding perfluoroalkyl iodide. The X-ray crystal structures of the toluidinium salts, [MeC(6)H(4)NH(3)](2)[C(2)F(5)PO(3)] and [MeC(6)H(4)NH(3)][C(8)F(17)P(O)(2)OH], are reported.

  8. New trends in nucleoside biotechnology.

    PubMed

    Mikhailopulo, I A; Miroshnikov, A I

    2010-07-01

    This review focuses on new trends in nucleoside biotechnology, which have emerged during the last decade. Continuously growing interest in the study of this class of compounds is fueled by a number of factors: ( i ) a growing need for large-scale production of natural 2 ' -deoxy- β -D-ribonucleosides as well as their analogs with modifications in the carbohydrate and base fragments, which can then be used for the synthesis and study of oligonucleotides, including short-interfering RNA (siRNA), microRNA (miRNA), etc.; ( ii ) a necessity for the development of efficient practical technologies for the production of biologically important analogs of natural nucleosides, including a number of anticancer and antiviral drugs; ( iii ) a need for further study of known and novel enzymatic transformations and their use as tools for the efficient synthesis of new nucloside analogs and derivates with biomedical potential. This article will review all of these aspects and also include a brief retrospect of this field of research.

  9. O-Nucleoside, S-Nucleoside, and N-Nucleoside Probes of Lumazine Synthase and Riboflavin Synthase

    PubMed Central

    Talukdar, Arindam; Zhao, Yujie; Lv, Wei; Bacher, Adelbert; Illarionov, Boris; Fischer, Markus; Cushman, Mark

    2012-01-01

    Lumazine synthase catalyzes the penultimate step in the biosynthesis of riboflavin, while riboflavin synthase catalyzes the last step. O-Nucleoside, S-nucleoside and N-nucleoside analogues of hypothetical lumazine biosynthetic intermediates have been synthesized in order to obtain structure and mechanism probes of these two enzymes, as well as inhibitors of potential value as antibiotics. Methods were devised for the selective cleavage of benzyl protecting groups in the presence of other easily reduced functionality by controlled hydrogenolysis over Lindlar catalyst. The deprotection reaction was performed in the presence of other reactive functionality including nitro groups, alkenes, and halogens. The target compounds were tested as inhibitors of lumazine synthase and riboflavin synthase obtained from a variety of microorganisms. In general, the S-nucleosides and N-nucleosides were more potent than the corresponding O-nucleosides as lumazine synthase and riboflavin synthase inhibitors, while the C-nucleosides were the least potent. A series of molecular dynamics simulations followed by free energy calculations using the Poisson-Boltzmann/surface area (MM-PBSA) method were carried out in order to rationalize the results of ligand binding to lumazine synthase, and the results provide insight into the dynamics of ligand binding as well as the molecular forces stabilizing the intermediates in the enzyme-catalyzed reaction. PMID:22780198

  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. Biocatalytic approaches applied to the synthesis of nucleoside prodrugs.

    PubMed

    Iglesias, Luis E; Lewkowicz, Elizabeth S; Medici, Rosario; Bianchi, Paola; Iribarren, Adolfo M

    2015-01-01

    Nucleosides are valuable bioactive molecules, which display antiviral and antitumour activities. Diverse types of prodrugs are designed to enhance their therapeutic efficacy, however this strategy faces the troublesome selectivity issues of nucleoside chemistry. In this context, the aim of this review is to give an overview of the opportunities provided by biocatalytic procedures in the preparation of nucleoside prodrugs. The potential of biocatalysis in this research area will be presented through examples covering the different types of nucleoside prodrugs: nucleoside analogues as prodrugs, nucleoside lipophilic prodrugs and nucleoside hydrophilic prodrugs.

  13. Nucleoside antibiotics: biosynthesis, regulation, and biotechnology.

    PubMed

    Niu, Guoqing; Tan, Huarong

    2015-02-01

    The alarming rise in antibiotic-resistant pathogens has coincided with a decline in the supply of new antibiotics. It is therefore of great importance to find and create new antibiotics. Nucleoside antibiotics are a large family of natural products with diverse biological functions. Their biosynthesis is a complex process through multistep enzymatic reactions and is subject to hierarchical regulation. Genetic and biochemical studies of the biosynthetic machinery have provided the basis for pathway engineering and combinatorial biosynthesis to create new or hybrid nucleoside antibiotics. Dissection of regulatory mechanisms is leading to strategies to increase the titer of bioactive nucleoside antibiotics.

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

    PubMed Central

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

    2012-01-01

    The phnD gene of Escherichia coli encodes the periplasmic binding protein of the phosphonate 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 ~70° 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 phosphonate uptake by bacteria and facilitated the rational design of high signal-to-noise phosphonate biosensors based both on coupled small molecule dyes and autocatalytic fluorescent proteins. PMID:22019591

  15. Selective Nucleoside Triphosphate Diphosphohydrolase-2 (NTPDase2) Inhibitors: Nucleotide Mimetics Derived from Uridine-5′-carboxamide†

    PubMed Central

    Brunschweiger, Andreas; Iqbal, Jamshed; Umbach, Frank; Scheiff, Anja B.; Munkonda, Mercedes N.; Sévigny, Jean; Knowles, Aileen F.; Müller, Christa E

    2016-01-01

    Ecto-nucleoside triphosphate diphosphohydrolases (E-NTPDases, subtypes 1, 2, 3, 8 of NTPDases) dephosphorylate nucleoside tri- and diphosphates to the corresponding di- and monophosphates. In the present study we synthesized adenine and uracil nucleotide mimetics, in which the phosphate residues were replaced by phosphonic acid esters attached to the nucleoside at the 5′-position by amide linkers. Among the synthesized uridine derivatives, we identified the first potent and selective inhibitors of human NTPDase2. The most potent compound was 19a (PSB-6426), which was a competitive inhibitor of NTPDase2 exhibiting a Ki value of 8.2 μM and selectivity versus other NTPDases. It was inactive toward uracil nucleotide-activated P2Y2, P2Y4, and P2Y6 receptor subtypes. Compound 19a was chemically and metabolically highly stable. In contrast to the few known (unselective) NTPDase inhibitors, 19a is an uncharged molecule and may be perorally bioavailable. NTPDase2 inhibitors have potential as novel cardioprotective drugs for the treatment of stroke and for cancer therapy. PMID:18630897

  16. 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...

  17. 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.

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

    PubMed

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

    2016-08-26

    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.

  19. Fluorinated nucleosides as antiviral and antitumor agents.

    PubMed

    Meng, Wei-Dong; Qing, Feng-Ling

    2006-01-01

    The synthesis of nucleosides and analogues with fluoride modifications on the surgar moiety are reviewed, and their biological activities as potential antiviral and anti-tumor agents are also discussed.

  20. [Phosphonate esterase activity in human serum (author's transl)].

    PubMed

    Labadie, M; Laplaud, P M; Lachatre, G; Breton, J C

    1980-02-01

    A simple methodology for the spectrophotometric assay of phosphonate esterase activity in human serum samples is described, featuring incubation at 30 degrees C in a medium containing p-nitrophenol and phenyl-phosphonic acid ester. Reproducibility of the method as well a mean values in normal patients vs age and sex are reported. Serum activity appears to be increased almost exclusively during pregnancy or administration of estrogenic drugs (as oral contraceptives or in prostate neoplasms).

  1. 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

  2. Exploring synthetic routes to nucleoside alkynylphosphonates.

    PubMed

    Meurillon, M; Peyrottes, S; Périgaud, C

    2008-01-01

    Alkynylphosphonates belong to a very interesting family as they may be viewed as precursors to a wide range of functionalized derivatives. Considering our ongoing research on 5'-mononucleotides of biological interest, we embarked on the synthesis of such compounds. Despite a limited number of steps, the nucleosidic pathway appeared disappointing. Therefore, an osidic pathway was explored and proved to be interesting. The corresponding optimization study and the synthesis of a new series of nucleoside alkynylphosphonates are described herein.

  3. The a-cycle problem for transverse Ising ring

    NASA Astrophysics Data System (ADS)

    Dong, Jian-Jun; Li, Peng; Chen, Qi-Hui

    2016-11-01

    Traditionally, the transverse Ising model is mapped to the fermionic c-cycle problem, which neglects the boundary effect due to thermodynamic limit. If persisting on a perfect periodic boundary condition, we can get a so-called a-cycle problem that has not been treated seriously so far (Lieb et al 1961 Ann. Phys. 16 407). In this work, we show a little surprising but exact result in this respect. We find the odevity of the number of lattice sites, N, in the a-cycle problem plays an unexpected role even in the thermodynamic limit, N\\to ∞ , due to the boundary constraint. We pay special attention to the system with N(\\in Odd)\\to ∞ , which is in contrast to the one with N(\\in Even)\\to ∞ , because the former suffers a ring frustration. As a new effect, we find the ring frustration induces a low-energy gapless spectrum above the ground state. By proving a theorem for a new type of Toeplitz determinant, we demonstrate that the ground state in the gapless region exhibits a peculiar longitudinal spin-spin correlation. The entangled nature of the ground state is also disclosed by the evaluation of its entanglement entropy. At low temperature, new behavior of specific heat is predicted. We also propose an experimental protocol for observing the new phenomenon due to the ring frustration.

  4. Catabolism of citronellol and related acyclic terpenoids in pseudomonads.

    PubMed

    Förster-Fromme, Karin; Jendrossek, Dieter

    2010-07-01

    Terpenes are a huge group of natural compounds characterised by their predominantly pleasant smell. They are built up by isoprene units in cyclic or acyclic form and can be functionalised by carbonyl, hydroxyl or carboxyl groups and by presence of additional carbon-carbon double bonds (terpenoids). Currently, much more than 10,000 terpenoid compounds are known, and many thereof are present in different iso- and stereoforms. Terpenoids are secondary metabolites and can have important biological functions in living organisms. In many cases, the biological functions of terpenoids are not known at all. Nevertheless, terpenoids are used in large quantities as perfumes and aroma compounds for food additives. Terpenoids can be also precursors and building blocks for synthesis of complex chiral compounds in chemical and pharmaceutical industry. Unfortunately, only few terpenoids are available in large quantities at reasonable costs. Therefore, characterisation of suited biocatalysts specific for terpenoid compounds and development of biotransformation processes of abundant terpenoids to commercially interesting derivates becomes more and more important. This minireview summarises knowledge on catabolic pathways and biotransformations of acyclic monoterpenes that have received only little attention. Terpenoids with 20 or more carbon atoms are not a subject of this study.

  5. Insights into Phosphate Cooperativity and Influence of Substrate Modifications on Binding and Catalysis of Hexameric Purine Nucleoside Phosphorylases

    PubMed Central

    de Giuseppe, Priscila O.; Martins, Nadia H.; Meza, Andreia N.; dos Santos, Camila R.; Pereira, Humberto D’Muniz; Murakami, Mario T.

    2012-01-01

    The hexameric purine nucleoside phosphorylase from Bacillus subtilis (BsPNP233) displays great potential to produce nucleoside analogues in industry and can be exploited in the development of new anti-tumor gene therapies. In order to provide structural basis for enzyme and substrates rational optimization, aiming at those applications, the present work shows a thorough and detailed structural description of the binding mode of substrates and nucleoside analogues to the active site of the hexameric BsPNP233. Here we report the crystal structure of BsPNP233 in the apo form and in complex with 11 ligands, including clinically relevant compounds. The crystal structure of six ligands (adenine, 2′deoxyguanosine, aciclovir, ganciclovir, 8-bromoguanosine, 6-chloroguanosine) in complex with a hexameric PNP are presented for the first time. Our data showed that free bases adopt alternative conformations in the BsPNP233 active site and indicated that binding of the co-substrate (2′deoxy)ribose 1-phosphate might contribute for stabilizing the bases in a favorable orientation for catalysis. The BsPNP233-adenosine complex revealed that a hydrogen bond between the 5′ hydroxyl group of adenosine and Arg43* side chain contributes for the ribosyl radical to adopt an unusual C3’-endo conformation. The structures with 6-chloroguanosine and 8-bromoguanosine pointed out that the Cl6 and Br8 substrate modifications seem to be detrimental for catalysis and can be explored in the design of inhibitors for hexameric PNPs from pathogens. Our data also corroborated the competitive inhibition mechanism of hexameric PNPs by tubercidin and suggested that the acyclic nucleoside ganciclovir is a better inhibitor for hexameric PNPs than aciclovir. Furthermore, comparative structural analyses indicated that the replacement of Ser90 by a threonine in the B. cereus hexameric adenosine phosphorylase (Thr91) is responsible for the lack of negative cooperativity of phosphate binding in this

  6. 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

  7. Delay estimation in a two-node acyclic network

    PubMed Central

    2009-01-01

    Linear measures such as cross-correlation have been used successfully to determine time delays from the given processes. Such an analysis often precedes identifying possible causal relationships between the observed processes. The present study investigates the impact of a positively correlated driver whose correlation function decreases monotonically with lag on the delay estimation in a two-node acyclic network with one and two-delays. It is shown that cross-correlation analysis of the given processes can result in spurious identification of multiple delays between the driver and the dependent processes. Subsequently, delay estimation of increment process as opposed to the original process under certain implicit constraints is explored. Short-range and long-range correlated driver processes along with those of their coarse-grained counterparts are considered. PMID:19214240

  8. Graphical presentation of confounding in directed acyclic graphs.

    PubMed

    Suttorp, Marit M; Siegerink, Bob; Jager, Kitty J; Zoccali, Carmine; Dekker, Friedo W

    2015-09-01

    Since confounding obscures the real effect of the exposure, it is important to adequately address confounding for making valid causal inferences from observational data. Directed acyclic graphs (DAGs) are visual representations of causal assumptions that are increasingly used in modern epidemiology. They can help to identify the presence of confounding for the causal question at hand. This structured approach serves as a visual aid in the scientific discussion by making underlying relations explicit. This article explains the basic concepts of DAGs and provides examples in the field of nephrology with and without presence of confounding. Ultimately, these examples will show that DAGs can be preferable to the traditional methods to identify sources of confounding, especially in complex research questions.

  9. Estimation of Sparse Directed Acyclic Graphs for Multivariate Counts Data

    PubMed Central

    Han, Sung Won; Zhong, Hua

    2016-01-01

    Summary The next-generation sequencing data, called high throughput sequencing data, are recorded as count data, which is generally far from normal distribution. Under the assumption that the count data follow the Poisson log-normal distribution, this paper provides an L1-penalized likelihood framework and an efficient search algorithm to estimate the structure of sparse directed acyclic graphs (DAGs) for multivariate counts data. In searching for the solution, we use iterative optimization procedures to estimate the adjacency matrix and the variance matrix of the latent variables. The simulation result shows that our proposed method outperforms the approach which assumes multivariate normal distributions, and the log-transformation approach. It also shows that the proposed method outperforms the rank-based PC method under sparse network or hub network structures. As a real data example, we demonstrate the efficiency of the proposed method in estimating the gene regulatory networks of the ovarian cancer study. PMID:26849781

  10. 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.

  11. 40 CFR 721.10412 - Phosphonic acid ester (generic) (P-07-706).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Phosphonic acid ester (generic) (P-07... Specific Chemical Substances § 721.10412 Phosphonic acid ester (generic) (P-07-706). (a) Chemical substance... phosphonic acid ester (PMN P-07-706) is subject to reporting under this section for the significant new...

  12. 40 CFR 721.10412 - Phosphonic acid ester (generic) (P-07-706).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Phosphonic acid ester (generic) (P-07... Specific Chemical Substances § 721.10412 Phosphonic acid ester (generic) (P-07-706). (a) Chemical substance... phosphonic acid ester (PMN P-07-706) is subject to reporting under this section for the significant new...

  13. 40 CFR 721.10412 - Phosphonic acid ester (generic) (P-07-706).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Phosphonic acid ester (generic) (P-07... Specific Chemical Substances § 721.10412 Phosphonic acid ester (generic) (P-07-706). (a) Chemical substance... phosphonic acid ester (PMN P-07-706) is subject to reporting under this section for the significant new...

  14. 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

  15. New structural forms in molecular metal phosphonates: novel tri- and hexanuclear zinc(II) cages containing phosphonate and pyrazole ligands.

    PubMed

    Chandrasekhar, Vadapalli; Kingsley, Savariraj; Rhatigan, Brian; Lam, Matthew K; Rheingold, Arnold L

    2002-03-11

    The reaction of ZnCl(2) with tert-butylphosphonic acid and 3,5-dimethylpyrazole in the presence of triethylamine as a hydrogen chloride scavenger affords a trinuclear molecular zinc phosphonate [Zn(3)Cl(2)(3,5-Me(2)Pz)(4)(t-BuPO(3))(2)]. The structure of this compound contains a planar trizinc assembly containing two bicapping mu(3) [t-BuPO(3)](2-) ligands and terminal pyrazole and chloride ligands. In contrast an analogous reaction of ZnCl(2) with phenylphosphonic acid and 3,5-dimethylpyrazole affords a hexanuclear zinc phosphonate [Zn(6)Cl(4)(3,5-Me(2)PzH)(8)(PhPO(3))(4)]. The six zinc centers are arranged in a chairlike conformation. The four phosphonates in this complex also act as bridging tripodal mu(3) [RPO(3)](2-) ligands.

  16. Enantioselective Pd-catalyzed allylation of acyclic α-fluorinated ketones.

    PubMed

    Wang, Wengui; Shen, Haiming; Wan, Xiao-Long; Chen, Qing-Yun; Guo, Yong

    2014-07-03

    Significant synthetic challenges remain for the asymmetric synthesis of tertiary α-fluoro ketones, which are potentially useful molecules for the development of drugs, agrochemicals, and functional materials. Herein, we describe the development of a method for the catalytic enantioselective synthesis of tertiary α-fluoro ketones via the Tsuji-Trost reaction of racemic acyclic α-fluorinated ketones. Enantioenriched acyclic α-cabonyl tertiary fluorides can be produced with the aid of a palladium/phosphinooxazoline catalyst.

  17. Nucleoside phosphorylation by the mineral schreibersite

    NASA Astrophysics Data System (ADS)

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

    2015-11-01

    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.

  18. Kipukasins: Nucleoside derivatives from Aspergillus versicolor.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Seven new aroyl uridine derivatives (kipukasins A-G; 1-7) were isolated from solid-substrate fermentation cultures of two different Hawaiian isolates of Aspergillus versicolor. The structures of compounds 1-7 were determined by analysis of NMR and MS data. The nucleoside portion of lead compound 1...

  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.

  20. Human equilibrative nucleoside transporter (ENT) family of nucleoside and nucleobase transporter proteins.

    PubMed

    Young, J D; Yao, S Y M; Sun, L; Cass, C E; Baldwin, S A

    2008-07-01

    1. The human (h) SLC29 family of integral membrane proteins is represented by four members, designated equilibrative nucleoside transporters (ENTs) because of the properties of the first-characterized family member, hENT1. They belong to the widely distributed eukaryotic ENT family of equilibrative and concentrative nucleoside/nucleobase transporter proteins. 2. A predicted topology of eleven transmembrane helices has been experimentally confirmed for hENT1. The best-characterized members of the family, hENT1 and hENT2, possess similar broad permeant selectivities for purine and pyrimidine nucleosides, but hENT2 also efficiently transports nucleobases. hENT3 has a similar broad permeant selectivity for nucleosides and nucleobases and appears to function in intracellular membranes, including lysosomes. 3. hENT4 is uniquely selective for adenosine, and also transports a variety of organic cations. hENT3 and hENT4 are pH sensitive, and optimally active under acidic conditions. ENTs, including those in parasitic protozoa, function in nucleoside and nucleobase uptake for salvage pathways of nucleotide synthesis and, in humans, are also responsible for the cellular uptake of nucleoside analogues used in the treatment of cancers and viral diseases. 4. By regulating the concentration of adenosine available to cell surface receptors, mammalian ENTs additionally influence physiological processes ranging from cardiovascular activity to neurotransmission.

  1. Thermus thermophilus Nucleoside Phosphorylases Active in the Synthesis of Nucleoside Analogues

    PubMed Central

    Almendros, Marcos; Sinisterra, Jose-Vicente

    2012-01-01

    Cells extracts from Thermus thermophilus HB27 express phosphorolytic activities on purines and pyrimidine nucleosides. Five putative encoding genes were cloned and expressed in Escherichia coli, and the corresponding recombinant proteins were purified and studied. Two of these showed phosphorolytic activities against purine nucleosides, and third one showed phosphorolytic activity against pyrimidine nucleosides in vitro, and the three were named TtPNPI, TtPNPII, and TtPyNP, respectively. The optimal temperature for the activity of the three enzymes was beyond the water boiling point and could not be measured accurately, whereas all of them exhibited a wide plateau of optimal pHs that ranged from 5.0 to 7.0. Analytical ultracentrifugation experiments revealed that TtPNPI was a homohexamer, TtPNPII was a monomer, and TtPyNP was a homodimer. Kinetic constants were determined for the phosphorolysis of the natural substrates of each enzyme. Reaction tests with nucleoside analogues revealed critical positions in the nucleoside for its recognition. Activities with synthetic nucleobase analogues, such as 5-iodouracil or 2,6-diaminopurine, and arabinosides were detected, supporting that these enzymes could be applied for the synthesis of new nucleoside analogs with pharmacological activities. PMID:22344645

  2. Modulators of Nucleoside Metabolism in the Therapy of Brain Diseases

    PubMed Central

    Boison, Detlev

    2010-01-01

    Nucleoside receptors are known to be important targets for a variety of brain diseases. However, the therapeutic modulation of their endogenous agonists by inhibitors of nucleoside metabolism represents an alternative therapeutic strategy that has gained increasing attention in recent years. Deficiency in endogenous nucleosides, in particular of adenosine, may causally be linked to a variety of neurological diseases and neuropsychiatric conditions ranging from epilepsy and chronic pain to schizophrenia. Consequently, augmentation of nucleoside function by inhibiting their metabolism appears to be a rational therapeutic strategy with distinct advantages: (i) in contrast to specific receptor modulation, the increase (or decrease) of the amount of a nucleoside will affect several signal transduction pathways simultaneously and therefore have the unique potential to modify complex neurochemical networks; (ii) by acting on the network level, inhibitors of nucleoside metabolism are highly suited to fine-tune, restore, or amplify physiological functions of nucleosides; (iii) therefore inhibitors of nucleoside metabolism have promise for the “soft and smart” therapy of neurological diseases with the added advantage of reduced systemic side effects. This review will first highlight the role of nucleoside function and dysfunction in physiological and pathophysiological situations with a particular emphasis on the anticonvulsant, neuroprotective, and antinociceptive roles of adenosine. The second part of this review will cover pharmacological approaches to use inhibitors of nucleoside metabolism, with a special emphasis on adenosine kinase, the key regulator of endogenous adenosine. Finally, novel gene-based therapeutic strategies to inhibit nucleoside metabolism and focal treatment approaches will be discussed. PMID:21401494

  3. 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.

  4. 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...

  5. 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...

  6. Nucleoside uptake in rat liver parenchymal cells.

    PubMed Central

    Mercader, J; Gomez-Angelats, M; del Santo, B; Casado, F J; Felipe, A; Pastor-Anglada, M

    1996-01-01

    Rat liver parenchymal cells express Na(+)-dependent and Na(+)- independent nucleoside transport activity. The Na(+)-dependent component shows kinetic properties and substrate specificity similar to those reported for plasma membrane vesicles [Ruiz-Montasell, Casado, Felipe and Pastor-Anglada (1992) J. Membr. Biol. 128, 227-233]. This transport activity shows apparent K(m) values for uridine in the range 8-13 microM and a Vmax of 246 pmol of uridine per 3 min per 10(5) cells. Most nucleosides, including the analogue formycin B, cis-inhibit Na(+)-dependent uridine transport, although thymidine and cytidine are poor inhibitors. Inosine and adenosine inhibit Na(+)-dependent uridine uptake in a dose-dependent manner, reaching total inhibition. Guanosine also inhibits Na(+)-dependent uridine uptake, although there is some residual transport activity (35% of the control values) that is resistant to high concentrations of guanosine but may be inhibited by low concentrations of adenosine. The transport activity that is inhibited by high concentrations of thymidine is similar to the guanosine-resistant fraction. These observations are consistent with the presence of at least two Na(+)-dependent transport systems. Na(+)-dependent uridine uptake is sensitive to N-ethylmaleimide treatment, but Na(+)-independent transport is not. Nitrobenzylthioinosine (NBTI) stimulates Na(+)-dependent uridine uptake. The NBTI effect involves a change in Vmax, it is rapid, dose-dependent, does not need preincubation and can be abolished by depleting the Na+ transmembrane electrochemical gradient. Na(+)-independent uridine transport seems to be insensitive to NBTI. Under the same experimental conditions, NBTI effectively blocks most of the Na(+)-independent uridine uptake in hepatoma cells. Thus the stimulatory effect of NBTI on the concentrative nucleoside transporter of liver parenchymal cells cannot be explained by inhibition of nucleoside efflux. PMID:8760370

  7. 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.

  8. PQQ-dependent alcohol dehydrogenase (QEDH) of Pseudomonas aeruginosa is involved in catabolism of acyclic terpenes.

    PubMed

    Chattopadhyay, Ava; Förster-Fromme, Karin; Jendrossek, Dieter

    2010-04-01

    Growth of Pseudomonas aeruginosa on acyclic terpene alcohols such as geraniol depends on the presence of the atuRABCDEFGH gene cluster and a functional acyclic terpene utilisation (Atu) pathway. The proteins encoded by the atu gene cluster are necessary but not sufficient for growth on acyclic terpenes. Comparative 2-dimensional polyacrylamide gel electrophoresis of soluble P. aeruginosa proteins revealed the presence of an additional spot (besides Atu proteins) that is specifically expressed in geraniol cells but is absent in isovalerate-grown cells. The spot was identified as PA1982 gene product a pyrroloquinoline quinone (PQQ) dependent ethanol oxidoreductase (QEDH). Inactivation of PA1982 by insertion mutagenesis resulted in inability of the mutant to utilise ethanol and in reduced growth on geraniol. Growth on ethanol was restored by transferring an intact copy of the PA1982 gene into the mutant. The PA1982 gene product was purified from recombinant Escherichia coli and revealed PQQ-dependent oxidoreductase activity with a variety of substrates including acyclic terpene derivates at comparable V(max)-values. Our results show that QEDH participates in oxidation of acyclic terpene derivates in addition to the well-known function in ethanol metabolism.

  9. Nucleoside modification with boron clusters and their metal complexes.

    PubMed

    Wojtczak, Blazej A; Olejniczak, Agnieszka B; Lesnikowski, Zbigniew J

    2009-09-01

    General methods for the synthesis of nucleosides modified with borane clusters and metallacarborane complexes are presented. These include: (1) the click chemistry approach based on Huisgen 1,3-dipolar cycloaddition and (2) tethering of the metallacarborane group to the aglycone of a nucleoside via a dioxane ring opening in oxonium metallacarborane derivatives. The proposed methodologies broaden the availability of nucleoside-borane cluster conjugates and open up new areas for their applications.

  10. 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.

  11. Role of nucleoside diphosphate kinase in the activation of anti-HIV nucleoside analogs.

    PubMed

    Schneider, B; Sarfati, R; Deville-Bonne, D; Véron, M

    2000-06-01

    Nucleoside analogs are currently used in antiretrovirus therapies. The best known example is AZT one of the first drug to be used for the treatment of AIDS. However, only the triphosphate derivatives of these compounds act as substrates of the viral reverse transcriptase. Since they do not enter cells, nucleoside analogs are administered and phosphorylated by cellular kinases. The last step in this phosphorylation pathway is catalyzed by nucleoside diphosphate (NDP) kinase. The incorporation of the nucleoside triphosphates into nascent viral DNA chain results in termination of the elongation process. We have performed kinetics studies of the phosphorylation reaction by NDP kinase of dideoxynucleoside diphosphates such as 2',3'-dideoxy-3'-azidothymidine diphosphate (AZT-DP) and 2',3'-dideoxy-2',3'-didehydrothymidine diphosphate (d4T-DP). We show that the catalytic efficiency is strongly decreased and, therefore, that the reaction step catalyzed by NDP kinase constitutes a bottleneck in the processing pathway of anti-HIV compounds. In addition, the affinity of the analogs in the absence of catalysis was determined using a catalytically inactive NDP kinase mutant, showing a reduction of affinity by a factor of 2 to 30, depending on the analog. The structure of NDP kinase provides a structural explanation for these results. Indeed, all nucleoside analogs acting as chain terminators must lack a 3'-OH in the nucleotide deoxyribose. Unfortunately, this same substitution is detrimental for their capacity to be phosphorylated by NDP kinase. This defines the framework for the design of new nucleoside analogs with increased efficiency in antiretroviral therapies.

  12. Phosphorylation of nucleoside-metallacarborane and carborane conjugates by nucleoside kinases.

    PubMed

    Wojtczak, Blazej A; Olejniczak, Agnieszka B; Wang, Liya; Eriksson, Staffan; Lesnikowski, Zbigniew J

    2013-01-01

    A library of purine and pyrimidine nucleosides modified with carborane or metallacarborane boron clusters at different locations, consisting of new molecules as well as already described compounds, was prepared. The compounds were tested as substrates for human deoxynucleoside kinases. Some conjugates, with modification attached to N3 of thymidine via a linker containing the triazole moiety, were efficiently phosphorylated by cytosolic thymidine kinase 1 and mitochondrial thymidine kinase 2. Higher phosphorylation levels were observed with thymidine kinase 1, the phosphorylation of nucleosides modified with metallacarboranes was observed for the first time.

  13. 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.

  14. Phosphonate-hydroxyapatite hybrid compounds prepared by hydrothermal method

    NASA Astrophysics Data System (ADS)

    Agougui, H.; Aissa, A.; Maggi, S.; Debbabi, M.

    2010-12-01

    Calcium hydroxyapatite (CaHAp) was prepared in the presence of two alkylphosphonates, the tert-butyl phosphonic acid TBPOH and the 2-carboxyletylphosphonic acid 2-CEPA, by hydrothermal method at 120 °C for 15 h. The modification of hydroxyapatite by grafting organic moieties is confirmed by IR and NMR MAS ( 1H and 31P) spectroscopy and chemical analysis. X-ray powder diffraction patterns show that the incorporation of organic moieties induces a significant loss of the material crystallinity and a clear increase of the unit cell lattice parameter a as function of 2-CEPA grafting rate. The specific surface area (SSA) increases with increasing phosphonate amount especially for 2-CEPA. All techniques show the lower reactivity of TBPOH due to the steric effects of tert-butyl, whereas the 2-CEPA with a linear chain and double acidic functions is more reactive and can replace the OH - groups of the apatitic structure.

  15. 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.

  16. Some biochemical properties of an acyclic oligonucleotide analogue. A plausible ancestor of the DNA?

    NASA Astrophysics Data System (ADS)

    Merle, Liliane; Spach, Gérard; Merle, Yves; Sági, János; Szemzö, Attila

    1993-04-01

    As acyclic oligonucleotides have been suggested as a primitive model of DNA or RNA in prebiotic times, we compared some biochemical properties of these analogues to that of natural ones. Firstly, an acyclic analogue of deoxyribonucleoside triphosphates was tested as a potential substrate of enzymes intervening in nucleic acids synthesis. GlyTTP, a dTTP analogue with a missing 2'-methylene group is notaccepted as a substrate by either DNA polymerase or deoxynucleotidyl terminal transferase (TdT). Secondly, themodified dodecathymidylate (GlyT)12, the racemic acyclic sugar analogue of (dT)12, proved to be anefficient primer for DNA polymerase and TdT, though the associative properties of (GlyT)12 are very weak as shown by UV spectroscopy in phosphate buffer without magnesium chloride. But (GlyT)12 has the advantage to be 500-times more stable against hydrolysis by snake venom phosphodiesterase than the corresponding oligothymidylate.

  17. Genomics-Enabled Discovery of Phosphonate Natural Products and their Biosynthetic Pathways

    PubMed Central

    Ju, Kou-San; Doroghazi, James R.; Metcalf, William W.

    2014-01-01

    Phosphonate natural products have proven to be a rich source of useful pharmaceutical, agricultural and biotechnology products, whereas study of their biosynthetic pathways has revealed numerous intriguing enzymes that catalyze unprecedented biochemistry. Here we review the history of phosphonate natural product discovery, highlighting technological advances that have played a key role in the recent advances in their discovery. Central to these developments has been the application of genomics, which allowed discovery and development of a global phosphonate metabolic framework to guide research efforts. This framework suggests that the future of phosphonate natural products remains bright, with many new compounds and pathways yet to be discovered. PMID:24271089

  18. 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

  19. Molecular Basis for Resistance Against Phosphonate Antibiotics and Herbicides

    PubMed Central

    Chekan, Jonathan R.; Cogan, Dillon P.; Nair, Satish K.

    2015-01-01

    Research in recent years have illuminated data on the mechanisms and targets of phosphonic acid antibiotics and herbicides, including fosfomycin, glyphosate, fosmidomycin and FR900098. Here we review the current state of knowledge of the structural and biochemical characterization of resistance mechanisms against these bioactive natural products. Advances in the understanding of these resistance determinants have spurred knowledge-based campaigns aimed towards the design of derivatives that retain biological activity but are less prone to tolerance. PMID:26811741

  20. 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.

  1. 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

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

    PubMed

    Sun, Jing; Jiang, Xi; Siegmund, Aaron; Connolly, Michael D; Downing, Kenneth H; Balsara, Nitash P; Zuckermann, Ronald N

    2016-04-26

    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.

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

    PubMed Central

    Peck, Spencer C.

    2013-01-01

    Natural product biosynthesis has proven a fertile ground for the discovery of novel chemistry. Herein we review the progress made in elucidating the biosynthetic pathways of phosphonate and phosphinate natural products such as the antibacterial compounds dehydrophos and fosfomycin, the herbicidal phosphinothricin-containing peptides, and the antimalarial compound FR-900098. In each case, investigation of the pathway has yielded unusual, and often unprecedented, biochemistry. Likewise, recent investigations have uncovered novel ways to cleave the C-P bond to yield phosphate under phosphorus starvation conditions. These include the discovery of novel oxidative cleavage of the C-P 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 C-P 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

  4. 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.

  5. C5-Modified nucleosides exhibiting anticancer activity.

    PubMed

    Lee, Yoon-Suk; Park, Sun Min; Kim, Hwan Mook; Park, Song-Kyu; Lee, Kiho; Lee, Chang Woo; Kim, Byeang Hyean

    2009-08-15

    We describe (i) a simple method for the synthesis of C5-modified nucleosides from 5-iodo-2'-deoxyuridine and (ii) their activity against six types of human cancer cell lines (HCT15, MM231, NCI-H23, NUGC-3, PC-3, ACHN). We generated nitrile oxides in situ from oximes using a commercial bleaching agent; their cycloadditions with 5-ethynyl-2'-deoxyuridine yielded isoxazole derivatives possessing activity against the cancer cell lines. We synthesized several azides from benzylic bromides and their click reactions with 5-ethynyl-2'-deoxyuridine provided triazole derivatives.

  6. Diametric Stereocontrol in Dynamic Catalytic Reduction of Racemic Acyl Phosphonates: Divergence from α-Keto Ester Congeners

    PubMed Central

    Corbett, Michael T.; Johnson, Jeffrey S.

    2013-01-01

    An unexpected dichotomy was observed in the Ru-catalyzed asymmetric transfer hydrogenation of acyl phosphonates: reduction proceeded from the opposite face relative to that observed in the analogous reduction of α-keto esters. The first highly selective catalytic hydrogenation of acyl phosphonates was utilized in the dynamic kinetic resolution of α-aryl acyl phosphonates providing β-stereogenic α-hydroxy phosphonic acid derivatives. PMID:23297694

  7. 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...

  8. 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...

  9. 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...

  10. 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.

  11. Some acyclic analogues of nucleotides and their template-directed reactions

    NASA Technical Reports Server (NTRS)

    Tohidi, Mahrokh; Orgel, Leslie E.

    1989-01-01

    Bismonophosphoimidazolides of acyclic analogues of guanosine IV and adenosine V were synthesized. They undergo oligomerization in the presence of complementary polynucleotide templates. Details of their synthesis and their subsequent template- and nontemplate-directed reactions are described, and their possible relevance to the origin of life is discussed.

  12. Evidence for halogen bond covalency in acyclic and interlocked halogen-bonding receptor anion recognition

    DOE PAGES

    Robinson, Sean W.; Mustoe, Chantal L.; White, Nicholas G.; ...

    2014-12-05

    The synthesis and anion binding properties of novel halogen-bonding (XB) bis-iodotriazole-pyridinium-containing acyclic and [2]catenane anion host systems are described. The XB acyclic receptor displays selectivity for acetate over halides with enhanced anion recognition properties compared to the analogous hydrogen-bonding (HB) acyclic receptor. A reversal in halide selectivity is observed in the XB [2]catenane, in comparison to the acyclic XB receptor, due to the interlocked host’s unique three-dimensional binding cavity, and no binding is observed for oxoanions. Notable halide anion association constant values determined for the [2]catenane in competitive organic–aqueous solvent mixtures demonstrate considerable enhancement of anion recognition as compared tomore » the HB catenane analogue. X-ray crystallographic analysis of a series of halide catenane complexes reveal strong XB interactions in the solid state. These interactions were studied using Cl and Br K-edge X-ray Absorption Spectroscopy (XAS) indicating intense pre-edge features characteristic of charge transfer from the halide to its bonding partner (σAX←X–* ← X1s), and providing a direct measure of the degree of covalency in the halogen bond(s). Lastly, the data reveal that the degree of covalency is similar to that which is observed in transition metal coordinate covalent bonds. These results are supported by DFT results, which correlate well with the experimental data.« less

  13. Evidence for halogen bond covalency in acyclic and interlocked halogen-bonding receptor anion recognition

    SciTech Connect

    Robinson, Sean W.; Mustoe, Chantal L.; White, Nicholas G.; Brown, Asha; Thompson, Amber L.; Kennepohl, Pierre; Beer, Paul D.

    2014-12-05

    The synthesis and anion binding properties of novel halogen-bonding (XB) bis-iodotriazole-pyridinium-containing acyclic and [2]catenane anion host systems are described. The XB acyclic receptor displays selectivity for acetate over halides with enhanced anion recognition properties compared to the analogous hydrogen-bonding (HB) acyclic receptor. A reversal in halide selectivity is observed in the XB [2]catenane, in comparison to the acyclic XB receptor, due to the interlocked host’s unique three-dimensional binding cavity, and no binding is observed for oxoanions. Notable halide anion association constant values determined for the [2]catenane in competitive organic–aqueous solvent mixtures demonstrate considerable enhancement of anion recognition as compared to the HB catenane analogue. X-ray crystallographic analysis of a series of halide catenane complexes reveal strong XB interactions in the solid state. These interactions were studied using Cl and Br K-edge X-ray Absorption Spectroscopy (XAS) indicating intense pre-edge features characteristic of charge transfer from the halide to its bonding partner (σAX←X–* ← X1s), and providing a direct measure of the degree of covalency in the halogen bond(s). Lastly, the data reveal that the degree of covalency is similar to that which is observed in transition metal coordinate covalent bonds. These results are supported by DFT results, which correlate well with the experimental data.

  14. Acyclic water pentamer induces novel supramolecular ribbed sheet: Cooperativity and competitiveness of weak and covalent forces?

    NASA Astrophysics Data System (ADS)

    Jana, Atish Dipankar; Saha, Rajat; Mostafa, Golam

    2010-03-01

    The 1D chain complex [{Cu(II)(bpp)(malonate)(H 2O)}(H 2O) 4] n ( 1) (bpp = 1,3-bis(4-pyridyl)propane) self-assembles to form a 2D ribbed sheet stabilized by an acyclic pentameric water cluster, which in turn, influences the conformation of the bpp ligand.

  15. Acyclic sulfides, garlicnins L-1-L-4, E, and F, from Allium sativum.

    PubMed

    Nohara, Toshihiro; Fujiwara, Yukio; Ikeda, Tsuyoshi; Yamaguchi, Koki; Manabe, Hideyuki; Murakami, Kotaro; Ono, Masateru; Nakano, Daisuke; Kinjo, Junei

    2014-01-01

    Six novel acyclic sulfides, named garlicnins L-1-L-4 (1-4), E (5), and F (6), were isolated from the acetone extracts, with the ability to suppress M2 macrophage activation, of the bulbs of garlic (Allium sativum L.), and their chemical structures were characterized.

  16. 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...

  17. 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....

  18. 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....

  19. 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....

  20. 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⁺).

  1. Study on follicular characteristics, hormonal and biochemical profile in norgestomet+PMSG treated acyclic buffaloes

    PubMed Central

    Jerome, A.; Srivastava, S. K.; Sharma, R. K.

    2016-01-01

    This research was conducted to study the follicular dynamics, hormonal, biochemical profile and fertility response in acyclic and norgestomet+PMSG treated acyclic buffaloes in summer. The study animals were divided into two groups: group I [control (n=8): no treatment] and II [treatment group (n=15)]. In group II, seven animals were used for follicular biochemical and hormonal profile and eight animals for fertility studies following Crestar® (Intervet, France) treatment (day 0: Crestar® insertion; day 8: 500 IU PMSG; day 9: Crestar® removal; day 11 AI). Follicular fluid stradiol (E2) and progesterone (P4) in acyclic and pre-ovulatory follicle in study groups was significantly (P<0.01) higher than peripheral level. Peripheral E2 concentration, during pre-ovulatory period in group II was higher (P<0.05) than group I. Significant correlation between serum and follicular E2 was deduced (r=0.888; P<0.01) as significant difference in serum cholesterol content was shown between groups. Lower follicular total protein (P<0.05) in acyclic animals and higher follicular glucose (P<0.05) in treated group were concluded. Significant correlation (r=-0.770; P<0.05) was observed between follicular cholesterol and triglycerides. Follicular characteristics, post PMSG administration, differed significantly (0.83 ± 0.20 vs 1.32 ± 0.12; P<0.01) in all buffaloes exhibiting estrus, out of which four conceived. In conclusion, follicular hormonal and biochemical profile exhibits alteration in protein and glucose level between summer acyclic and treated buffaloes. However, peripheral E2 along with fertility response showed significant difference (P<0.01) between the study groups with significant correlation in E2, cholesterol and triglycerides between peripheral and follicular compartment. PMID:28224008

  2. Evidence that hyperprolactinaemia is associated with ovarian acyclicity in female zoo African elephants.

    PubMed

    Dow, T L; Brown, J L

    2012-01-01

    African elephants of reproductive age in zoos are experiencing high rates of ovarian cycle problems (>40%) and low reproductive success. Previously, our laboratory found that 1/3 of acyclic females exhibit hyperprolactinaemia, a likely cause of ovarian dysfunction. This follow-up study re-examined hyperprolactinaemia in African elephants and found the problem has increased significantly to 71% of acyclic females. Circulating serum progestagens and prolactin were analysed in 31 normal cycling, 13 irregular cycling and 31 acyclic elephants for 12 months. In acyclic females, overall mean prolactin concentrations differed from cycling females (P < 0.05), with concentrations being either higher (n = 22; 54.90 ± 13.31 ngmL(-1)) or lower (n = 9; 6.47 ± 1.73 ngmL(-1)) than normal. No temporal patterns of prolactin secretion were evident in elephants that lacked progestagen cycles. In cycling females, prolactin was secreted in a cyclical manner, with higher concentrations observed during nonluteal (34.38 ± 1.77 and 32.75 ± 2.61 ngmL(-1)) than luteal (10.51 ± 0.30 and 9.67 ± 0.42 ngmL(-1)) phases for normal and irregular females, respectively. Of most concern was that over two-thirds of acyclic females now are hyperprolactinemic, a dramatic increase over that observed 7 years earlier. Furthermore, females of reproductive age constituted 45% of elephants with hyperprolactinaemia. Until the cause of this problem is identified and a treatment is developed, reproductive rates will remain suboptimal and the population nonsustaining.

  3. Phosphorylation of anti-HIV nucleoside analogs by nucleoside diphosphate kinase.

    PubMed

    Schneider, B; Xu, Y; Sellam, O; Sarfati, R; Janin, J; Véron, M; Deville-Bonne, D

    1999-01-01

    The reaction of NDP kinase with antiviral nucleoside triphosphates used in antiviral therapies was studied at the presteady state by fluorescence stopped-flow and compared with the steady-state parameters. The affinity of the analogs was determined by fluorescence titration of a mutated enzyme with an inserted Trp in the binding site. The lack of the 3' hydroxyl in analogs is shown to decrease the kcat more than the KD.

  4. 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.

  5. 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.

  6. Acyclonucleosides, modified seco-nucleosides, and salicyl- or catechol-derived acyclic 5-fluorouracil O,N-acetals: antiproliferative activities, cellular differentiation and apoptosis.

    PubMed

    Marchal, Juan A; Núñez, María C; Aránega, Antonia; Gallo, Miguel A; Espinosa, Antonio; Campos, Joaquín M

    2009-01-01

    The goal of cancer chemotherapy with classical drugs - the destruction of the tumor cells - is often complicated by significant toxicity. As an alternative, induced differentiation modulates the cell programme by transforming malignant cells into mature cells with no proliferative potential. Our data demonstrate that (+/-)-1-{[3-(2-hydroxyethoxy)-1-isopropoxy]propyl}-5-fluorouracil inhibits proliferation, induces myogenic differentiation, increases the expression of proteins specifically present in normally differentiated skeletal muscle cells, and modifies the adhesion capacity of these cells against the rhabdomyosarcoma cell line RD. From a designing point of view, a benzene ring was fused to the side chain in order to increase the lipophilicity and anticancer activity of our molecules. Herein we report the preparation and biological activity of three compounds having the general formula (+/-)-1-[2-(5-substituted-2-hydroxybenzyloxy)-1-methoxyethyl]-5-fluorouracils. A catechol-derived compound such as (+/-)-1-[3-(2-hydroxyphenoxy)-1-methoxypropyl]-5-fluorouracil and two salicyl-derived compounds such as (+/-)-(Z)-1-[4-(2-hydroxyphenyl)-1-methoxy-but-3-enyl]-5-fluorouracil [(Z)-43] and its dihydrogenated derivative (+/-)-1-[4-(2-hydroxyphenyl)-1-methoxybutyl]-5-fluorouracil were prepared to complete the set of six O,N-acetals. The most active compound against the MCF-7 breast cancer cell line was (+/-)-(Z)-43 with an IC(50) = 9.40 +/- 0.64 microM. Differentiated breast cancer cells generate fat deposits within the cytoplasm. The MCF-7 cells trea-ed with (+/-)-(Z)-43 caused an increase in the lipid content over control cells after 3 days of treatment. Our results suggest that there may be significant potential advantages in the use of this new differentiating agent for the treatment of breast cancer.

  7. 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

    2006-01-05

    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.

  8. 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

  9. Highly π electron-rich macro-aromatics: bis(p-aminophenyl)-carbo-benzenes and their DBA acyclic references.

    PubMed

    Rives, Arnaud; Baglai, Iaroslav; Malytskyi, Volodymyr; Maraval, Valérie; Saffon-Merceron, Nathalie; Voitenko, Zoia; Chauvin, Remi

    2012-09-11

    A series of stable quadrupolar bis(p-aminophenyl)-carbo-benzenes, featuring both donor-donor-donor π-frustration and central macro-aromaticity, is described and compared to the acyclic dibutatrienylacetylene (DBA) reference series.

  10. Palladium-catalyzed modification of unprotected nucleosides, nucleotides, and oligonucleotides.

    PubMed

    Shaughnessy, Kevin H

    2015-05-22

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

  11. Improving nucleoside analogs via lipid conjugation: Is fatter any better?

    PubMed

    Alexander, Peter; Kucera, Gregory; Pardee, Timothy S

    2016-04-01

    In the past few decades, nucleoside analog drugs have been used to treat a large variety of cancers. These anti-metabolite drugs mimic nucleosides and interfere with chain lengthening upon incorporation into the DNA or RNA of actively replicating cells. However, efficient delivery of these drugs is limited due to their pharmacokinetic properties, and tumors often develop drug resistance. In addition, nucleoside analogs are generally hydrophilic, resulting in poor bioavailability and impaired blood-brain barrier penetration. Conjugating these drugs to lipids modifies their pharmacokinetic properties and may improve in vivo efficacy. This review will cover recent advances in the field of conjugation of phospholipids to nucleoside analogs. This includes conjugation of myristic acid, 12-thioethyldodecanoic acid, 5-elaidic acid esters, phosphoramidate, and self-emulsifying formulations. Relevant in vitro and in vivo data will be discussed for each drug, as well as any available data from clinical trials.

  12. 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.

  13. Screening of a minimal enriched P450 BM3 mutant library for hydroxylation of cyclic and acyclic alkanes.

    PubMed

    Weber, Evelyne; Seifert, Alexander; Antonovici, Mihaela; Geinitz, Christopher; Pleiss, Jürgen; Urlacher, Vlada B

    2011-01-21

    A minimal enriched P450 BM3 library was screened for the ability to oxidize inert cyclic and acyclic alkanes. The F87A/A328V mutant was found to effectively hydroxylate cyclooctane, cyclodecane and cyclododecane. F87V/A328F with high activity towards cyclooctane hydroxylated acyclic n-octane to 2-(R)-octanol (46% ee) with high regioselectivity (92%).

  14. Alterations in follicular fluid estradiol, progesterone and insulin concentrations during ovarian acyclicity in water buffalo (Bubalus bubalis).

    PubMed

    Khan, F A; Das, G K; Pande, Megha; Sarkar, M; Mahapatra, R K; Shankar, Uma

    2012-01-01

    Ovarian acyclicity is one of the most important causes of infertility in water buffalo. Recent studies have indicated alterations in the composition of follicular fluid during the condition. The aim of this study was to determine the changes in follicular fluid concentrations of estradiol, progesterone and insulin during ovarian acyclicity in water buffalo. Ovaries were collected from 50 acyclic and 95 cyclic (control) buffaloes and follicular fluid was aspirated from small (5.0-6.9 mm), medium (7.0-9.9 mm) and large (≥10.0 mm) sized follicles. Estradiol concentration was lower (P<0.0001) in acyclic (1.4 ± 0.09 ng/ml) than in cyclic (3.3 ± 0.18 ng/ml) buffaloes. Regardless of the ovarian cyclic status, there was an increase (P<0.01) in estradiol concentration with the increase in follicle size; the mean concentrations were 2.4 ± 0.16 ng/ml, 2.8 ± 0.29 ng/ml and 3.5 ± 0.41 ng/ml in small, medium and large follicles, respectively. A higher (P<0.001) progesterone concentration was recorded in acyclic (24.3 ± 2.61 ng/ml) compared to the cyclic (7.6 ± 0.79 ng/ml) group. Furthermore, acyclic buffaloes had a lower (P<0.05) concentration of insulin in the follicular fluid than that of cyclic buffaloes (15.2 ± 1.55 μIU/ml versus 25.9 ± 2.78 μIU/ml, respectively). In conclusion, acyclic buffaloes have lower concentrations of estradiol and insulin concurrent with higher concentrations of progesterone in the follicular fluid. These hormonal changes in the follicular microenvironment are possibly a manifestation of the disturbances in the normal follicular development leading to anovulation and anestrus in acyclic buffaloes.

  15. The nucleoside uridine isolated in the gas phase.

    PubMed

    Peña, Isabel; Cabezas, Carlos; Alonso, José L

    2015-03-02

    Herein we present the first experimental observation of the isolated nucleoside uridine, placed in the gas phase by laser ablation and characterized by Fourier transform (FT) microwave techniques. Free from the bulk effects of their native environments, anti/C2'-endo-g+ conformation has been revealed as the most stable form of uridine. Intramolecular hydrogen bonds involving uracil and ribose moieties have been found to play an important role in the stabilization of the nucleoside.

  16. The Nucleoside Uridine Isolated in the Gas Phase**

    PubMed Central

    Peña, Isabel; Cabezas, Carlos; Alonso, José L.

    2016-01-01

    Herein we present the first experimental observation of the isolated nucleoside uridine, placed in the gas phase by laser ablation and characterized by Fourier transform microwave techniques. Free from the bulk effects of their native environments, anti/C2’-endo-g+ conformation has been revealed as the most stable form of uridine. Intramolecular hydrogen bonds involving uracil and ribose moieties have been found to play an important role in the stabilization of the nucleoside. PMID:25683559

  17. Enantioselective Heck arylations of acyclic alkenyl alcohols using a redox-relay strategy.

    PubMed

    Werner, Erik W; Mei, Tian-Sheng; Burckle, Alexander J; Sigman, Matthew S

    2012-12-14

    Progress in the development of asymmetric Heck couplings of arenes and acyclic olefins has been limited by a tenuous understanding of the factors that dictate selectivity in migratory insertion and β-hydride elimination. On the basis of key mechanistic insight recently garnered in the exploration of selective Heck reactions, we report here an enantioselective variant that delivers β-, γ-, or δ-aryl carbonyl products from acyclic alkenol substrates. The catalyst system imparts notable regioselectivity during migratory insertion and promotes the migration of the alkene's unsaturation toward the alcohol to ultimately form the ketone product. The reaction uses aryldiazonium salts as the arene source, yields enantiomeric products from opposite starting alkene configurations, and uses a readily accessible ligand. The racemic nature of the alkenol substrate does not bias the enantioselection.

  18. Antimalarial action of nitrobenzylthioinosine in combination with purine nucleoside antimetabolites.

    PubMed

    Gero, A M; Scott, H V; O'Sullivan, W J; Christopherson, R I

    1989-04-01

    The infection of human erythrocytes by two strains of the human malarial parasite, Plasmodium falciparum (FCQ-27 or the multi-drug-resistant strain K-1), markedly changed the transport characteristics of the nucleosides, adenosine and tubercidin, compared to uninfected erythrocytes. A component of the transport of these nucleosides was insensitive to the classical mammalian nucleoside transport inhibitor nitrobenzylthioinosine (NBMPR). In vitro studies with tubercidin demonstrated ID50 values of 0.43 and 0.51 microM for FCQ-27 and K-1, respectively. In addition, the nucleoside transport inhibitors NBMPR, nitrobenzylthioguanosine (NBTGR), dilazep and dipyridamole also independently exhibited antimalarial activity in vitro. The combination of tubercidin and NBMPR or NBTGR in vitro demonstrated synergistic activity, whilst tubercidin together with dilazep or dipyridamole showed subadditive activity. Analysis by HPLC indicated that NBMPR could permeate the infected cell membrane and provided evidence for the catabolism of NBMPR in vitro, with subsequent alteration of the purine pool in the infected erythrocyte. These observations further indicated the possibility of the utilization of cytotoxic nucleosides against P. falciparum infection in conjunction with a nucleoside transport inhibitor to protect the host tissue.

  19. Acyclic ketones in the defensive secretion of a "daddy longlegs" (Leiobunum vittatum).

    PubMed

    Meinwald, J; Kluge, A F; Carrel, J E; Eisner, T

    1971-07-01

    The defensive secretion of the "daddy longlegs" Leiobunum vittatum was analyzed and found to contain the acyclic ketones 4-methylheptan-3-one and E-4,6-dimethyl-6-octen-3-one as its major organic components. Although 4-methylheptan-3-one has been found previously as an alarm substance in certain ant genera, the second component, whose structure is confirmed by synthesis, is new.

  20. 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...

  1. Preliminary assessment of developmental toxicity of Perfluorinated Phosphonic Acid 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. These emerging chemicals have recently been detected in the environment, particularl...

  2. 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.

  3. Nanocomposites of phosphonic-acid-functionalized polyethylenes with inorganic quantum dots.

    PubMed

    Rünzi, Thomas; Baier, Moritz C; Negele, Carla; Krumova, Marina; Mecking, Stefan

    2015-01-01

    Insertion of diethyl vinyl phosphonates and free vinyl phosphonic acid, respectively, into [(P^O)Pd(Me)(dmso)] ((P^O) = κ(2)-P,O-Ar2PC6H4SO2O with Ar = 2-MeOC6H4) (1-dmso) occurs in a 2,1- as well as 1,2-fashion, to form a four-and a five-membered chelate [(P^O)Pd{κ(2)-C,O-CH(P(O)(OR)2)CH2CH3}] and [(P^O)Pd{κ(2)-C,O-CH2CH(P(O)(OR)2)CH3}] (R = H, Et). No decomposition or other reactions of 1 by free phosphonic acid moieties occur. Copolymerization in a pressure reactor by 1-dmso yields linear random poly(ethylene-co-diethyl vinyl phosphonate) and poly(ethylene-co-vinyl phosphonic acid). In these copolymerizations, reversible coordination of the phosphonate moieties of free monomer as well as chelate formation by incorporated monomer retards chain growth as also evidenced by relative binding studies of diethyl phosphonate towards 1. Post-polymerization emulsification of poly(ethylene-co-vinyl phosphonic acid) together with CdSe/CdS quantum dots (QDs) yields submicron (ca. 50 nm from dynamic light scattering (DLS) and transmission electron microscopy (TEM)) polymer particles with the QDs embedded in the functionalized polyethylene in a nonaggregated fashion. This embedding benefits the fluorescence behavior in terms of continuous emission and life-time as revealed by wide-field fluorescence measurements. These composite particle dispersions are employed as a ″masterbatch" together with an aqueous high density polyethylene (HDPE) dispersion to generate thin films (by spin-coating) and bulk materials (from the melt), respectively, in which the inorganic nanoparticles remain highly disperse.

  4. 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

  5. Phosphonic acid functionalized poly(pentafluorostyrene) as polyelectrolyte membrane for fuel cell application

    NASA Astrophysics Data System (ADS)

    Atanasov, Vladimir; Oleynikov, Andrey; Xia, Jiabing; Lyonnard, Sandrine; Kerres, Jochen

    2017-03-01

    In this paper we introduce polyelectrolyte membranes based on phosphonated poly(pentafluorostyrene) (PPFS) and their performances in a fuel cell. The polyelectrolytes were obtained via partial phosphonation of PPFS varying the phosphonation degree from 17 to 66%. These membranes showed a high resistance to temperature (Tdecomp. = 355-381 °C) and radical attack (96-288 h in Fenton's test). A blend membrane consisting of 82 wt% fully phosphonated PPFS and 18 wt% poly(benzimidazole) is compared to the 66% phosphonated membrane having similar ion-conductivity (σ = 57 mS cm-1 at 120 °C, 90% RH). In the fuel cell the blend showed the best performance reaching 0.40 W cm-2 against 0.34 W cm-2 for the 42 wt% phosphonated membrane and 0.35 W cm-2 for Nafion 212. Furthermore, the blend maintained its operation at potentiostatic regime (0.5 V) for 620 h without declining in its performance. The highest power density of 0.78 W cm-2 was reached for the blend with a thickness of 15 μm using humidified oxygen (RH > 90%) at the cathode side. The switch from humidified to dry gasses during operation reduced the current density down to 0.6 A cm-2, but the cell maintained under operation for 66 h.

  6. 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

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

    PubMed

    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 (31)P 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.

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

    PubMed

    Lee, Michael W; Parker, William B; Xu, Bo

    2013-09-26

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

  9. Rhodium carbene routes to oxazoles and thiazoles. Catalyst effects in the synthesis of oxazole and thiazole carboxylates, phosphonates, and sulfones.

    PubMed

    Shi, Baolu; Blake, Alexander J; Lewis, William; Campbell, Ian B; Judkins, Brian D; Moody, Christopher J

    2010-01-01

    Dirhodium tetraacetate catalyzed reaction of alpha-diazo-beta-keto-carboxylates and -phosphonates with arenecarboxamides gives 2-aryloxazole-4-carboxylates and 4-phosphonates by carbene N-H insertion and cyclodehydration. In stark contrast, dirhodium tetrakis(heptafluorobutyramide) catalysis results in a dramatic change of regioselectivity to give oxazole-5-carboxylates and 5-phosphonates. Alpha-diazo-beta-ketosulfones behave similarly and give 5-sulfonyloxazoles upon dirhodium tetrakis(heptafluorobutyramide) catalyzed reaction with carboxamides. The analogous reactions of thiocarboxamides give the corresponding thiazole-5-carboxylates, -phosphonates, and -sulfones.

  10. 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

  11. Follicular characteristics and intrafollicular concentrations of nitric oxide and ascorbic acid during ovarian acyclicity in water buffalo (Bubalus bubalis).

    PubMed

    Khan, Firdous Ahmad; Das, Goutam Kumar

    2012-01-01

    The objective of this study was to examine the follicular characteristics and intrafollicular concentrations of nitric oxide and ascorbic acid during ovarian acyclicity in buffaloes. Ovaries were collected from 56 acyclic and 95 cyclic buffaloes at slaughter, surface follicle number was counted and follicles were classified into small (5.0-6.9 mm), medium (7.0-9.9 mm), and large (≥ 10.0 mm) size categories based on their diameter. Follicular fluid was aspirated and assayed for nitric oxide, ascorbic acid, estradiol, and progesterone. Acyclic buffaloes had a higher (P<0.05) number of medium-sized follicles and a lower (P<0.001) number of large follicles than the cyclic ones. In acyclic animals, the number of large follicles was lower (P<0.01) than in medium size category which in turn was lower (P<0.001) than the number of small follicles. In contrast, the number of medium and large follicles was not different (P>0.05) in the cyclic control. However, the number of small-sized follicles was higher (P<0.001) compared to the other two categories. The incidence of large-sized follicles was lower (P<0.05) in acyclic buffalo population compared to the cyclic control. Evaluation of estrogenic status demonstrated that all the follicles of acyclic buffaloes are estrogen-inactive (E (2)/P (4) ratio<1). Small- and medium-sized follicles of acyclic buffaloes had higher concentrations of nitric oxide (P<0.05 and P<0.001, respectively) and lower concentrations of ascorbic acid (P<0.05 and P<0.01, respectively) than the corresponding size estrogen-active follicles of their cyclic counterparts. In conclusion, this study indicates that follicular development continues during acyclicity in buffaloes. Although follicles in some acyclic buffaloes attain a size corresponding to morphological dominance, they are unable to achieve functional dominance, perhaps due to an altered balance of intrafollicular nitric oxide and ascorbic acid and, as a result, these follicles instead of

  12. 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.

  13. A review on the chemical synthesis of pyrophosphate bonds in bioactive nucleoside diphosphate analogs.

    PubMed

    Xu, Zhihong

    2015-09-15

    Currently, there is an ongoing interest in the synthesis of nucleoside diphosphate analogs as important regulators in catabolism/anabolism, and their potential applications as mechanistic probes and chemical tools for bioassays. However, the pyrophosphate bond formation step remains as the bottleneck. In this Digest, the chemical synthesis of the pyrophosphate bonds of representative bioactive nucleoside diphosphate analogs, i.e. phosphorus-modified analogs, nucleoside cyclic diphosphates, and nucleoside diphosphate conjugates, will be described.

  14. Next generation macrocyclic and acyclic cationic lipids for gene transfer: Synthesis and in vitro evaluation.

    PubMed

    Jubeli, Emile; Maginty, Amanda B; Abdul Khalique, Nada; Raju, Liji; Abdulhai, Mohamad; Nicholson, David G; Larsen, Helge; Pungente, Michael D; Goldring, William P D

    2015-10-01

    Previously we reported the synthesis and in vitro evaluation of four novel, short-chain cationic lipid gene delivery vectors, characterized by acyclic or macrocyclic hydrophobic regions composed of, or derived from, two 7-carbon chains. Herein we describe a revised synthesis of an expanded library of related cationic lipids to include extended chain analogues, their formulation with plasmid DNA (pDNA) and in vitro delivery into Chinese hamster ovarian (CHO-K1) cells. The formulations were evaluated against each other based on structural differences in the hydrophobic domain and headgroup. Structurally the library is divided into four sets based on lipids derived from two 7- or two 11-carbon hydrophobic chains, C7 and C11 respectively, which possess either a dimethylamine or a trimethylamine derived headgroup. Each set includes four cationic lipids based on an acyclic or macrocyclic, saturated or unsaturated hydrophobic domain. All lipids were co-formulated with the commercial cationic lipid 1,2-dimyristoyl-sn-glycero-3-ethylphosphocholine (EPC) in a 1:1 molar ratio, along with one of two distinct neutral co-lipids, cholesterol or 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) in an overall cationic-to-neutral lipid molar ratio of 3:2. Binding of lipid formulations with DNA, and packing morphology associated with the individual lipid-DNA complexes were characterized by gel electrophoresis and small angle X-ray diffraction (SAXD), respectively. As a general trend, lipoplex formulations based on mismatched binary cationic lipids, composed of a shorter C7 lipid and the longer lipid EPC (C14), were generally associated with higher transfection efficiency and lower cytotoxicity than their more closely matched C11/EPC binary lipid formulation counterparts. Furthermore, the cyclic lipids gave transfection levels as high as or greater than their acyclic counterparts, and formulations with cholesterol exhibited higher transfection and lower cytotoxicity than those

  15. 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.

  16. 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

  17. 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

  18. Nucleoside H-boranophosphonates: synthesis and properties of a new class of nucleotide analogs.

    PubMed

    Higashida, Renpei; Kawanaka, Toshihide; Oka, Natsuhisa; Wada, Takeshi

    2007-01-01

    Nucleoside H-boranophosphonates were synthesized via the condensation reactions of appropriately protected nucleosides with monopyridinium H-boranophosphonate. The condensation reactions gave only the mono-esterified products under the optimized conditions without formation of di-esterified byproducts. Deprotection of the condensation products was achieved under basic conditions to afford the fully-deprotected nucleoside H-boranophosphonates in excellent yields.

  19. Synthesis of L-enantiomers of 4'-thioarabinofuranosyl pyrimidine nucleosides.

    PubMed

    Satoh, H; Yoshimura, Y; Sakata, S; Miura, S; Machida, H; Matsuda, A

    1998-05-05

    L-Enantiomers of 4'-thioarabinofuranosyl pyrimidine nucleosides were synthesized from D-xylose. Methyl 2,3,5-tri-O-benzyl-D-xylofuranoside 6 was converted to the corresponding xylitol 7, which was treated with MsCl and then Na2S to give 1,4-anhydro-L-4-thioarabitol 8. As previously reported, Pummerer rearrangement of 8 followed by glycosylation with a silylated thymine and N4-acetylcytosine derivative and deprotection gave the corresponding alpha- and beta-L-4'-thioarabinofuranosyl pyrimidine nucleosides.

  20. New prodrugs based on phospholipid-nucleoside conjugates

    SciTech Connect

    MacCoss, M.

    1982-02-03

    A method is described for the preparation of defined, isomerically pure phospholipid-nucleoside conjugates as a prodrug in which the drug (araC) is attached to the phospholipid by a monophosphate linkage. Key intermediates in the process involve selective blocking and deblocking of the nucleoside derivative. These particular monophosphate-linked derivatives represent a new class of prodrug, which are useful by themselves or in combination with diphosphate linked derivatives. Several new compositions involving diphosphate linked derivatives are described in which the products are isomerically pure and having defined fatty acid chain lengths.

  1. Neutral losses: a type of important variables in prediction of branching degree for acyclic alkenes from mass spectra.

    PubMed

    Zhang, Liangxiao; Fan, Wei; Cao, Dongsheng; Zeng, Maomao; Xiao, Hongbin; Liang, Yizeng

    2012-03-30

    Neutral losses are a type of important variables in mass spectral interpretation. Since it is hard to calculate or extract neutral losses from mass spectra, they are usually discarded. In this study, dissimilarity analysis was employed to extract mass spectral characteristics for predicting branching degree of acyclic alkenes. The relationships between branching degree and neutral loss were constructed under direction of experimental observation and mass spectral fragmentations. A branching degree predictor of acyclic alkenes was subsequently built based on the above relationships. After tested by the experimental data in previous studies, the predictor could correctly provide the branching degree from abundant ions of mass spectra. More importantly, this predictor was able to point out which acyclic alkenes could be predicted correctly or not.

  2. Homo- and heteroexchange of adenine nucleotides and nucleosides in rat hippocampal slices by the nucleoside transport system

    PubMed Central

    Sperlágh, Beáta; Szabó, Gábor; Erdélyi, Ferenc; Baranyi, Mária; Sylvester Vizi, E

    2003-01-01

    Here, we investigated how nucleotides and nucleosides affect the release of tritiated purines and endogenous adenosine 5′-triphosphate (ATP) from superfused rat hippocampal slices. ATP elicited concentration-dependent [3H]purine efflux from slices preloaded with [3H]adenosine. High-performance liquid chromatography analysis of the effluent showed that the tritium label represented the whole set of adenine nucleotides and nucleosides, and ATP significantly increased the outflow of [3H]ATP. Adenosine 5′-diphosphate, adenosine, uridine, uridine 5′-triphosphate, α,β-methylene-ATP and 3′-O-(4-benzoylbenzoyl)-ATP were also active in eliciting [3H]purine release. Adenosine (300 μM) also evoked endogenous ATP efflux from the hippocampal slices. Reverse transcription-coupled-polymerase chain reaction analysis revealed that mRNAs encoding a variety of P2X and P2Y receptor proteins are expressed in the rat hippocampus. Nevertheless, neither P2 receptor (i.e. pyridoxal-5-phosphate-6-azophenyl-2′,4′-disulphonic acid, 30 μM, suramin, 300 μM and reactive blue 2, 10 μM), nor adenosine receptor (8-cyclopentyl-1,3-dipropylxanthine, 250 nM and dimethyl-1-propargylxanthine, 250 nM) antagonists modified the effect of ATP (300 μM) to evoke [3H]purine release. The nucleoside transport inhibitors, dipyridamole (10 μM), nitrobenzylthioinosine (10 μM) and adenosine deaminase (2–10 U ml−1), but not the ecto-adenylate kinase inhibitor diadenosine pentaphosphate (200 μM) significantly reduced ATP-evoked [3H]purine efflux. In summary, we found that ATP and other nucleotides and nucleosides promote the release of one another and themselves by the nucleoside transport system. This action could have relevance during physiological and pathological elevation of extracellular purine levels high enough to reverse the nucleoside transporter. PMID:12788822

  3. Phosphonate-anchored monolayers for antibody binding to magnetic nanoparticles.

    PubMed

    Benbenishty-Shamir, Helly; Gilert, Roni; Gotman, Irena; Gutmanas, Elazar Y; Sukenik, Chaim N

    2011-10-04

    Targeted delivery of magnetic iron oxide nanoparticles (IONPs) to a specific tissue can be achieved by conjugation with particular biological ligands on an appropriately functionalized IONP surface. To take best advantage of the unique magnetic properties of IONPs and to maximize their blood half-life, thin, strongly bonded, functionalized coatings are required. The work reported herein demonstrates the successful application of phosphonate-anchored self-assembled monolayers (SAMs) as ultrathin coatings for such particles. It also describes a new chemical approach to the anchoring of antibodies on the surface of SAM-coated IONPs (using nucleophilic aromatic substitution). This anchoring strategy results in stable, nonhydrolyzable, covalent attachment and allows the reactivity of the particles toward antibody binding to be activated in situ, such that prior to the activation the modified surface is stable for long-term storage. While the SAMs do not have the well-packed crystallinity of other such monolayers, their structure was studied using smooth model substrates based on an iron oxide layer on a double-side polished silicon wafer. In this way, atomic force microscopy, ellipsometry, and contact angle goniometry (tools that could not be applied to the nanoparticles' surfaces) could contribute to the determination of their monomolecular thickness and uniformity. Finally, the successful conjugation of IgG antibodies to the SAM-coated IONPs such that the antibodies retain their biological activity is verified by their complexation to a secondary fluorescent antibody.

  4. Reactions of (chloroethynyl)phosphonates with neutral nucleophiles

    SciTech Connect

    Garibina, V.A.; Leonov, A.A.; Dogadina, A.V.; Ionin, B.I.; Petrov, A.A.

    1987-12-20

    The authors studied reactions of (chloroethynyl)phosphonates with a number of neutral nucleophiles containing a primary amino group together with a second nucleophilic center. The phosphorylated benzimidazoles are crystalline substances. The chemical shift of phosphorus in these compounds, delta/sub p/ +22.0 ppm, is characteristic for compounds containing an sp/sup 3/-hybridized carbon atom attached to phosphorus. The PMR spectra of the compounds contain a characteristic signal of the protons of a methylene group attached to phosphorus, delta 2.8, /sup 2/J/sub HP/ 22.0 Hz. The /sup 13/C NMR spectrum of the compounds contain the signals of a methoxy group on phosphorus delta/sub C/(CH/sub 3/O) 49.50 ppm, J/sub CP/ 6.9 Hz; and a doublet signal of the carbon atom of the methylene group delta/sub C/ 23.16 ppm, J/sub CP/ 138.8 Hz; and a doublet of carbon of the benzimidazole ring delta/sub C/ 141.6 ppm, J/sub CP/ 8.7 Hz; the carbon atoms of the benzene ring resonate in the weak field.

  5. SF2312 is a natural phosphonate inhibitor of Enolase

    PubMed Central

    Maxwell, David; Lin, Yu-Hsi; Hammoudi, Naima; Peng, Zhenghong; Pisaneschi, Federica; Link, Todd M.; Lee, Gilbert R.; Sun, Duoli; Prasad, Basvoju A. Bhanu; Di Francesco, Maria Emilia; Czako, Barbara; Asara, John M.; Wang, Y. Alan; Bornmann, William; DePinho, Ronald A.; Muller, Florian L.

    2016-01-01

    Despite being critical for energy generation in most forms of life, few if any microbial antibiotics specifically inhibit glycolysis. To develop a specific inhibitor of the glycolytic enzyme Enolase 2 for the treatment of cancers with deletion of Enolase 1, we modeled the synthetic tool compound inhibitor, Phosphonoacetohydroxamate (PhAH) into the active site of human ENO2. A ring-stabilized analogue of PhAH, with the hydroxamic nitrogen linked to the alpha-carbon by an ethylene bridge, was predicted to increase binding affinity by stabilizing the inhibitor in a bound conformation. Unexpectedly, a structure based search revealed that our hypothesized back-bone-stabilized PhAH bears strong similarity to SF2312, a phosphonate antibiotic of unknown mode of action produced by the actinomycete Micromonospora, which is active under anaerobic conditions. Here, we present multiple lines of evidence, including a novel X-ray structure, that SF2312 is a highly potent, low nM inhibitor of Enolase. PMID:27723749

  6. Sorption of Perfluoroalkyl Phosphonates and Perfluoroalkyl Phosphinates in Soils.

    PubMed

    Lee, Holly; Mabury, Scott Andrew

    2017-02-22

    Perfluoroalkyl phosphonates (PFPAs) and perfluoroalkyl phosphinates (PFPiAs) are recently discovered perfluoroalkyl acids (PFAAs) that have been widely detected in house dust, aquatic biota, surface water, and wastewater environments. The sorption of C6, C8, and C10 monoalkylated PFPAs and C6/C6, C6/C8, and C8/C8 dialkylated PFPiAs was investigated in seven soils of varying geochemical parameters. Mean distribution coefficients, logKd*, ranged from 0.2 to 2.1 for the PFPAs and PFPiAs and were generally observed to increase with perfluoroalkyl chain length. The logKd* of PFPiAs calculated here (1.6-2.1) were similar to those previously measured for the longer-chain perfluorodecane sulfonate (1.9, PFDS) and perfluoroundecanoate (1.7, PFUnA) in sediments, but overall when compared as a class, were greater than those for the perfluoroalkane sulfonates (-0.8-1.9, PFSAs), perfluoroalkyl carboxylates (-0.4-1.7, PFCAs), and PFPAs (0.2-1.5). No single soil-specific parameter, such as pH and organic carbon content, was observed to control the sorption of PFPAs and PFPiAs, the lack of which may be attributed to competing interferences in the naturally heterogeneous soils. The PFPAs were observed to desorb to a greater extent and likely circulate as aqueous contaminants in the environment, while the more sorptive PFPiAs would be preferentially retained by environmental solid phases.

  7. 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.

  8. 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.

  9. A novel acyclic oligomycin A derivative formed via retro-aldol rearrangement of oligomycin A.

    PubMed

    Lysenkova, Lyudmila N; Turchin, Konstantin F; Korolev, Alexander M; Bykov, Evgenyi E; Danilenko, Valery N; Bekker, Olga B; Trenin, Alexey S; Elizarov, Sergei M; Dezhenkova, Lyubov G; Shtil, Alexander A; Preobrazhenskaya, Maria N

    2012-08-01

    The antibiotic oligomycin A in the presence of K(2)CO(3) and n-Bu(4)NHSO(4) in chloroform in phase-transfer conditions afforded a novel derivative through the initial retro-aldol fragmentation of the 8,9 bond, followed by further transformation of the intermediate aldehyde. NMR, MS and quantum chemical calculations showed that the novel compound is the acyclic oligomycin A derivative, in which the 8,9 carbon bond is disrupted and two polyfunctional branches are connected with spiroketal moiety in positions C-23 and C-25. The tri-O-acetyl derivative of the novel derivative was prepared. The acyclic oligomycin A derivative retained the ability to induce apoptosis in tumor cells at low micromolar concentrations, whereas its antimicrobial potencies decreased substantially. The derivative virtually lost the inhibitory activity against F(0)F(1) ATP synthase-containing proteoliposomes, strongly suggesting the existence of the target(s) beyond F(0)F(1) ATP synthase that is important for the antitumor potency of oligomycin A.

  10. Drude polarizable force field for aliphatic ketones and aldehydes, and their associated acyclic carbohydrates

    NASA Astrophysics Data System (ADS)

    Small, Meagan C.; Aytenfisu, Asaminew H.; Lin, Fang-Yu; He, Xibing; MacKerell, Alexander D.

    2017-02-01

    The majority of computer simulations exploring biomolecular function employ Class I additive force fields (FF), which do not treat polarization explicitly. Accordingly, much effort has been made into developing models that go beyond the additive approximation. Development and optimization of the Drude polarizable FF has yielded parameters for selected lipids, proteins, DNA and a limited number of carbohydrates. The work presented here details parametrization of aliphatic aldehydes and ketones (viz. acetaldehyde, propionaldehyde, butaryaldehyde, isobutaryaldehyde, acetone, and butanone) as well as their associated acyclic sugars (uc(d)-allose and uc(d)-psicose). LJ parameters are optimized targeting experimental heats of vaporization and molecular volumes, while the electrostatic parameters are optimized targeting QM water interactions, dipole moments, and molecular polarizabilities. Bonded parameters are targeted to both QM and crystal survey values, with the models for ketones and aldehydes shown to be in good agreement with QM and experimental target data. The reported heats of vaporization and molecular volumes represent a compromise between the studied model compounds. Simulations of the model compounds show an increase in the magnitude and the fluctuations of the dipole moments in moving from gas phase to condensed phases, which is a phenomenon that the additive FF is intrinsically unable to reproduce. The result is a polarizable model for aliphatic ketones and aldehydes including the acyclic sugars uc(d)-allose and uc(d)-psicose, thereby extending the available biomolecules in the Drude polarizable FF.

  11. 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...

  12. 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...

  13. 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...

  14. 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.

  15. Intranuclear protein transduction through a nucleoside salvage pathway.

    PubMed

    Hansen, James E; Tse, Chung-Ming; Chan, Grace; Heinze, Emil R; Nishimura, Robert N; Weisbart, Richard H

    2007-07-20

    Regulation of gene expression by intranuclear transduction of macromolecules such as transcription factors is an alternative to gene therapy for the treatment of numerous diseases. The identification of an effective intranuclear delivery vehicle and pathway for the transport of therapeutic macromolecules across plasma and nuclear membranes, however, has posed a significant challenge. The anti-DNA antibody fragment 3E10 Fv has received attention as a novel molecular delivery vehicle due to its penetration into living cells with specific nuclear localization, absence of toxicity, and successful delivery of therapeutic cargo proteins in vitro and in vivo. Elucidation of the pathway that allows 3E10 Fv to cross cell membranes is critical to the development of new molecular therapies. Here we show that 3E10 Fv penetrates cells through a nucleoside salvage transporter. 3E10 Fv is unable to penetrate into cells deficient in the equilibrative nucleoside transporter ENT2, and reconstitution of ENT2 into ENT2-deficient cells restores 3E10 Fv transport into cell nuclei. Our results represent the first demonstration of protein transport through a nucleoside salvage pathway. We expect that our finding will facilitate a variety of methods of gene regulation in the treatment of human diseases, open up new avenues of research in nucleoside salvage pathways, and enhance our understanding of the pathophysiology of autoimmune diseases.

  16. 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

  17. A Broad Specificity Nucleoside Kinase from Thermoplasma acidophilum

    PubMed Central

    Elkin, Sarah R.; Kumar, Abhinav; Price, Carol W.; Columbus, Linda

    2012-01-01

    The crystal structure of Ta0880, determined at 1.91 A resolution, from Thermoplasma acidophilum revealed a dimer with each monomer composed of an α/β /α sandwich domain and a smaller lid domain. The overall fold belongs to the PfkB family of carbohydrate kinases (a family member of the Ribokinase clan) which include ribokinases, 1-phosphofructokinases, 6-phosphofructo-2-kinase, inosine/guanosine kinases, frutokinases, adenosine kinases, and many more. Based on its general fold, Ta0880 had been annotated as a ribokinase-like protein. Using a coupled pyruvate kinase/lactate dehydrogenase assay, the activity of Ta0880 was assessed against a variety of ribokinase/pfkB-like family substrates; activity was not observed for ribose, fructose-1-phosphate, or fructose-6-phosphate. Based on structural similarity with nucleoside kinases (NK) from Methanocaldococcus jannaschii (MjNK, PDB 2C49 and 2C4E) and Burkholderia thailandensis (BtNK, PDB 3B1O), nucleoside kinase activity was investigated. Ta0880 (TaNK) was confirmed to have nucleoside kinase activity with an apparent KM for guanosine of 0.21 μM and catalytic efficiency of 345,000 M−1 s−1. These three NKs have significantly different substrate, phosphate donor, and cation specificities and comparisons of specificity and structure identified residues likely responsible for the nucleoside substrate selectivity. Phylogenetic analysis identified three clusters within the PfkB family and indicates that TaNK represents a new sub-family with broad nucleoside specificities. PMID:23161756

  18. A broad specificity nucleoside kinase from Thermoplasma acidophilum.

    PubMed

    Elkin, Sarah R; Kumar, Abhinav; Price, Carol W; Columbus, Linda

    2013-04-01

    The crystal structure of Ta0880, determined at 1.91 Å resolution, from Thermoplasma acidophilum revealed a dimer with each monomer composed of an α/β/α sandwich domain and a smaller lid domain. The overall fold belongs to the PfkB family of carbohydrate kinases (a family member of the Ribokinase clan) which include ribokinases, 1-phosphofructokinases, 6-phosphofructo-2-kinase, inosine/guanosine kinases, fructokinases, adenosine kinases, and many more. Based on its general fold, Ta0880 had been annotated as a ribokinase-like protein. Using a coupled pyruvate kinase/lactate dehydrogenase assay, the activity of Ta0880 was assessed against a variety of ribokinase/pfkB-like family substrates; activity was not observed for ribose, fructose-1-phosphate, or fructose-6-phosphate. Based on structural similarity with nucleoside kinases (NK) from Methanocaldococcus jannaschii (MjNK, PDB 2C49, and 2C4E) and Burkholderia thailandensis (BtNK, PDB 3B1O), nucleoside kinase activity was investigated. Ta0880 (TaNK) was confirmed to have nucleoside kinase activity with an apparent KM for guanosine of 0.21 μM and catalytic efficiency of 345,000 M(-1) s(-1) . These three NKs have significantly different substrate, phosphate donor, and cation specificities and comparisons of specificity and structure identified residues likely responsible for the nucleoside substrate selectivity. Phylogenetic analysis identified three clusters within the PfkB family and indicates that TaNK is a member of a new sub-family with broad nucleoside specificities. Proteins 2013. © 2012 Wiley Periodicals, Inc.

  19. Synthesis of (α,α-difluoropropargyl)phosphonates via aldehyde-to-alkyne homologation.

    PubMed

    Pajkert, Romana; Röschenthaler, Gerd-Volker

    2013-04-19

    An efficient synthetic methodology to a series of novel alkynes bearing a difluoromethylenephosphonate function via a Corey-Fuchs-type sequence starting from (diethoxyphosphoryl)difluoroacetic aldehyde is described. Dehydrobromination of the intermediate (3,3-dibromodifluoroallyl)phosphonate with potassium tert-butoxide gave rise to the corresponding bromoalkyne, whereas upon treatment with lithium base, the generation of ((diethoxyphosphoryl)difluoropropynyl)lithium has been achieved for the first time. The synthetic potential of this lithium reagent was further demonstrated by its reactions with selected electrophiles such as aldehydes, ketones, triflates, chlorophosphines, and chlorosilanes, leading to the corresponding propargyl phosphonates in good to excellent yields. However, in the case, of sterically hindered aldehydes, (α-fluoroallenyl)phosphonates were the solely isolated products.

  20. Photochromic Terbium Phosphonates with Photomodulated Luminescence and Metal Ion Sensitive Detection.

    PubMed

    Yang, Weiting; Tian, Hong-Rui; Li, Jian-Ping; Hui, Yuan-Feng; He, Xiang; Li, Jiyang; Dang, Song; Xie, Zhigang; Sun, Zhong-Ming

    2016-10-17

    Rational selection and modification of rare earth metal centers and photoactive organic linkers enables designable multiphotofunctionality to come to fruition in new hybrid coordination polymer materials. By using a viologen-functionalized diphosphonate linker, two terbium phosphonate compounds (Tb-1 and Tb-2) have been constructed, which display reversible photochromic reactions in response to UV light and soft X-ray irradiation. In addition, the photo-induced electron-transfer reaction can modulate the luminescent emission to thus realize photoluminescence switching behavior. Furthermore, both terbium phosphonates can serve as highly sensitive sensors to probe Cu(2+) in solution through their luminescence. Thus, they represent the first photochromic examples of lanthanide phosphonate-based materials with photomodulated luminescence and sensitive detection of metal ions.

  1. Layered Calcium Structures of p-Phosphonic Acid O-Methyl-Calix[6]arene

    PubMed Central

    Clark, Thomas E.; Martin, Adam; Makha, Mohamed; Sobolev, Alexandre N.; Su, Dian; Rohrs, Henry W.; Gross, Michael L.; Raston, Colin L.

    2010-01-01

    Hexamethoxy-calix[6]arene has been fully functionalized with p-phosphonic acid groups on the upper rim in 57% yield over three steps, and has been authenticated in the solid state by X-ray diffraction as either a nitrate salt or one of two calcium complexes. The latter differ by the ratio of calcium ions per calixarene, either 3:1 or 4:1. In both structures the coordination sphere of the calcium ions is made up of oxygen atoms from the phosphonic acid groups and from water of crystallization, as part of extended polymeric layers in the extended 3D packing. Hirshfeld surface analysis shows extensive O…H and O…Ca interactions for the phosphonic acid moieties in both calcium structures. MALDI-TOF MS of the hexaphosphonic acid shows nano-arrays consisting of up to a maximum of 28 calixarene units. PMID:20657793

  2. 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.

  3. 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

  4. Intermediate temperature proton conductors for PEM fuel cells based on phosphonic acid as protogenic group: a progress report.

    PubMed

    Steininger, H; Schuster, M; Kreuer, K D; Kaltbeitzel, A; Bingöl, B; Meyer, W H; Schauff, S; Brunklaus, G; Maier, J; Spiess, H W

    2007-04-21

    The melting behaviour and transport properties of straight chain alkanes mono- and difunctionalized with phosphonic acid groups have been investigated as a function of their length. The increase of melting temperature and decrease of proton conductivity with increasing chain length is suggested to be the consequence of an increasing ordering of the alkane segments which constrains the free aggregation of the phosphonic acid groups. However, the proton mobility is reduced to a greater extent than the proton diffusion coefficient indicating an increasing cooperativity of proton transport with increasing length of the alkane segment. The results clearly indicate that the "spacer concept", which had been proven successful in the optimization of the proton conductivity of heterocycle based systems, fails in the case of phosphonic acid functionalized polymers. Instead, a very high concentration of phosphonic acid functional groups forming "bulky" hydrogen bonded aggregates is suggested to be essential for obtaining very high proton conductivity. Aggregation is also suggested to reduce condensation reactions generally observed in phosphonic acid containing systems. On the basis of this understanding, the proton conductivities of poly(vinyl phosphonic acid) and poly(meta-phenylene phosphonic acid) are discussed. Though both polymers exhibit a substantial concentration of phosphonic acid groups, aggregation seems to be constrained to such an extent that intrinsic proton conductivity is limited to values below sigma = 10(-3) S cm(-1) at T = 150 degrees C. The results suggest that different immobilization concepts have to be developed in order to minimize the conductivity reduction compared to the very high intrinsic proton conductivity of neat phosphonic acid under quasi dry conditions. In the presence of high water activities, however, (as usually present in PEM fuel cells) the very high ion exchange capacities (IEC) possible for phosphonic acid functionalized ionomers (IEC

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

    NASA Astrophysics Data System (ADS)

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

    2016-10-01

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

  6. [Application of phosphates and phosphonates prodrugs in drug research and development].

    PubMed

    Ji, Xun; Wang, Jiang; Zhang, Lei; Zhao, Lin-Xiang; Jiang, Hua-Liang; Liu, Hong

    2013-05-01

    Based on the character of the molecular structure, the prodrugs of phosphates and phosphonates were divided into two categories. The first is the drug which contained the phosphate group, introducing protected groups to increase lipophilicity and improve bioavailability. The other one is the drug which had no phosphate group, introducing the phosphate group into molecules to enhance the solubility, regulate the distribution coefficient and enhance the drug-like property. This review focuses on the application of phosphates and phosphonates in drug research and development based on improvement of physico-chemical property, drug safety and the pharmacokinetics.

  7. Preparation, characterization, and modeling of α-zirconium phosphonates with ether-functional surfaces

    PubMed Central

    Furman, Benjamin R.; Wellinghoff, Stephen T.; Thompson, Paul M.; Beall, Gary W.; Laine, Richard M.; Rawls, H. Ralph

    2009-01-01

    Layered α-zirconium(IV) phosphonates were prepared from novel ether-terminal alkyl phosphonic acids, providing nanoplatelets with brush-like polar surfaces. The precursor materials were characterized by NMR, mass spectrometry, and elemental analysis. The derived nanoparticles were examined by XRD, TEM, TGA, and elemental analysis. The experimental compositions were slightly rich in organophosphorus content. In general, the layered materials had good crystallinity, with layer reflections appearing up to (005) and d-spacings consistent with the anticipated α-phase structure. Computer simulations suggest that tailored surface chemistries, including ether functionalities, will offer favorable thermodynamic interactions with polyester polymer matrices. PMID:20090854

  8. 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.

  9. 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.

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

    NASA Astrophysics Data System (ADS)

    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.

  11. 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.

  12. Pd-Catalyzed N-Arylation of Secondary Acyclic Amides: Catalyst Development, Scope, and Computational Study

    PubMed Central

    Hicks, Jacqueline D.; Hyde, Alan M.; Cuezva, Alberto Martinez; Buchwald, Stephen L.

    2009-01-01

    We report the efficient N-arylation of acyclic secondary amides and related nucleophiles with aryl nonaflates, triflates, and chlorides. This method allows for easy variation of the aromatic component in tertiary aryl amides. A new biaryl phosphine with P-bound 3,5-(bis)trifluoromethylphenyl groups was found to be uniquely effective for this amidation. The critical aspects of the ligand were explored through synthetic, mechanistic, and computational studies. Systematic variation of the ligand revealed the importance of (1) a methoxy group on the aromatic carbon of the “top ring” ortho to the phosphorus and (2) two highly electron-withdrawing P-bound 3,5-(bis)trifluoromethylphenyl groups. Computational studies suggest the electron-deficient nature of the ligand is important in facilitating amide binding to the LPd(II)(Ph)(X) intermediate. PMID:19886610

  13. New acyclic secondary metabolites from the biologically active fraction of Albizia lebbeck flowers.

    PubMed

    Al-Massarani, Shaza M; El Gamal, Ali A; Abd El Halim, Mohamed F; Al-Said, Mansour S; Abdel-Kader, Maged S; Basudan, Omer A; Alqasoumi, Saleh I

    2017-01-01

    The total extract of Albizia lebbeck flowers was examined in vivo for its possible hepatoprotective activity in comparison with the standard drug silymarin at two doses. The higher dose expressed promising activity especially in reducing the levels of AST, ALT and bilirubin. Fractionation via liquid-liquid partition and reexamination of the fractions revealed that the n-butanol fraction was the best in improving liver biochemical parameters followed by the n-hexane fraction. However, serum lipid parameters were best improved with CHCl3 fraction. The promising biological activity results initiated an intensive chromatographic purification of A. lebbeck flowers fractions. Two compounds were identified from natural source for the first time, the acyclic farnesyl sesquiterpene glycoside1-O-[6-O-α-l-arabinopyranosyl-β-d-glucopyranoside]-(2E,6E-)-farnesol (6) and the squalene derivative 2,3-dihydroxy-2,3-dihydrosqualene (9), in addition to eight compounds reported here for the first time from the genus Albizia; two benzyl glycosides, benzyl 1-O-β-d-glucopyranoside (1) and benzyl 6-O-α-l-arabinopyranosyl β-d-glucopyranoside (2); three acyclic monoterpene glycosides, linalyl β-d-glucopyranoside (3) and linalyl 6-O-α-l-arabinopyranosyl-β-d-glucopyranoside (4); (2E)-3,7-dimethylocta-2,6-dienoate-6-O-α-l arabinopyranosyl-β-d-glucopyranoside (5), two oligoglycosides, n-hexyl-α-l arabinopyranosyl-(1 → 6)-β-d-glucopyranoside (creoside) (7) and n-octyl α-l-arabinopyranosyl-(1 → 6)-β-d-glucopyranoside (rhodiooctanoside) (8); and ethyl fructofuranoside (10). The structures of the isolated compounds were elucidated based on extensive examination of their spectroscopic 1D and 2D-NMR, MS, UV, and IR data. It is worth mentioning that, some of the isolated linalol glycoside derivatives were reported as aroma precursors.

  14. Distorted cubic tetranuclear vanadium(IV) phosphonate cages: double-four-ring (D4R) containing transition metal ion phosphonate cages.

    PubMed

    Chandrasekhar, Vadapalli; Dey, Atanu; Senapati, Tapas; Sañudo, E Carolina

    2012-01-21

    The reaction of VCl(3) with 3,5-dimethylpyrazole (3,5-Me(2)PzH) and trichloromethylphosphonic/tert-butylphosphonic acid in the presence of triethylamine as a hydrogen chloride scavenger afforded the tetranuclear V(IV) assemblies, [(VO)(4)(3,5-Me(2)PzH)(8)(CCl(3)PO(3))(4)] (1) and [(VO)(4)(3,5-Me(2)PzH)(4)(t-BuPO(3))(4)] (2). Both of these compounds possess a distorted cubic framework structures containing V(IV) ions and phosphorus atoms in the alternate corners of the cube. The edges of the cube contain oxygen atoms derived from the phosphonate ligand. The phosphonate ligand in both of these compounds is dianionic and helps to bind to three V(IV) centers. The faces of the cubic ensembles contain puckered V(2)P(2)O(4) eight-membered rings. The V(IV) center in 1 is six-coordinate in a distorted octahedral geometry while in 2 it is five-coordinate in a distorted square-pyramidal geometry. Magnetic studies carried out on 1 and 2 reveal that the V(IV) centers are anti-ferromagnetically coupled to each other, albeit weakly, through the mediation of the phosphonate ligands.

  15. 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.

  16. Coupling between catalysis and oligomeric structure in nucleoside diphosphate kinase.

    PubMed

    Mesnildrey, S; Agou, F; Karlsson, A; Bonne, D D; Véron, M

    1998-02-20

    A dimeric Dictyostelium nucleoside diphosphate kinase has been stabilized by the double mutation P100S-N150stop which targets residues involved in the trimer interface (Karlsson, A., Mesnildrey, S., Xu, Y., Moréra, S., Janin, J., and Veron, M. (1996) J. Biol. Chem. 271, 19928-19934). The reassociation of this dimeric form into a hexamer similar to the wild-type enzyme is induced by the presence of a nucleotide substrate. Equilibrium sedimentation and gel filtration experiments, as well as enzymatic activity measurements, show that reactivation of the enzyme closely parallels its reassociation. A phosphorylatable intermediate with low activity participates in the association pathway while the dimeric form is shown totally devoid of enzymatic activity. Our results support the hypothesis that different oligomeric species of nucleoside diphosphate kinase are involved in different cellular processes where the enzymatic activity is not required.

  17. Compositions containing nucleosides and manganese and their uses

    DOEpatents

    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.

  18. Synthesis and cytostatic activity of purine nucleosides derivatives of allofuranose.

    PubMed

    Besada, Pedro; Costas, Tamara; Teijeira, Marta; Terán, Carmen

    2010-12-01

    Several new purine nucleosides derivatives of allofuranose were prepared according to Vorbrüggen method, starting from 1,2,5,6-di-O-isopropylidene-α-D-allofuranose and using 1,2,3,5,6-pentaacetoxy-β-D-allofuranose as key intermediate. The synthesized allofuranosyl nucleosides, as well as some acetyl derivatives, were evaluated for their cytotoxicity in vitro in three human cancer cell lines (MCF-7, Hela-229 and HL-60). Among the studied compounds the 9-(2,3,5,6-tetra-O-acetyl-β-D-allofuranosyl)-2,6-dichloropurine (9) was the most potent one on the three cell lines evaluated, being its activity against HL-60 cells similar to cisplatin.

  19. Purification and characterization of purine nucleoside phosphorylase from Proteus vulgaris.

    PubMed Central

    Surette, M; Gill, T; MacLean, S

    1990-01-01

    Purine nucleoside phosphorylase was isolated and purified from cell extracts of Proteus vulgaris recovered from spoiling cod fish (Gadus morhua). The molecular weight and isoelectric point of the enzyme were 120,000 +/- 2,000 and pH 6.8. The Michaelis constant for inosine as substrate was 3.9 x 10(-5). Guanosine also served as a substrate (Km = 2.9 x 10(-5). However, the enzyme was incapable of phosphorylizing adenosine. Adenosine proved to be useful as a competitive inhibitor and was used as a ligand for affinity chromatography of purine nucleoside phosphorylase following initial purification steps of gel filtration and ion-exchange chromatography. PMID:2111121

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

    PubMed

    Feduchi, E; Cosín, M; Carrasco, L

    1985-03-01

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

  1. 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

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

    NASA Technical Reports Server (NTRS)

    Lohrmann, R.

    1975-01-01

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

  3. 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.

  4. Metabolism of Pyrimidines and Pyrimidine Nucleosides by Salmonella typhimurium

    PubMed Central

    Beck, Christoph F.; Ingraham, John L.; Neuhard, Jan; Thomassen, Elisabeth

    1972-01-01

    The pathways by which uracil, cytosine, uridine, cytidine, deoxyuridine, and deoxycytidine are metabolized by Salmonella typhimurium are established. The various 5-fluoropyrimidine analogues are shown to exert their toxic effects only after having been converted to the nucleotide level, and these conversions are shown to be catalyzed by the same enzymes which similarly convert the natural substrates. Methods for isolating mutant strains blocked in various steps of metabolism of pyrimidine bases and nucleosides are described. PMID:4259664

  5. Nucleoside analog labeling of neural stem cells and their progeny.

    PubMed

    DeBoer, Erik Michael; Rasin, Mladen-Roko

    2013-01-01

    Nucleoside analog pulse labeling is an important technique which can assess the birthdate, cell cycle maintenance, or cycling rates of cells during development. This method has evolved over several decades of use and is now applied to a multitude of tissue subtypes and systems. The methodology in this chapter covers the classic uses for analog pulse labeling as well as their use in conjunction with the newly characterized technique of in utero electroporation (IUE).

  6. Evaluation of Anti-HIV-1 Mutagenic Nucleoside Analogues*

    PubMed Central

    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

  7. 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

  8. Transport of 3,4-dihydroxybutyl-1-phosphonate, an analogue of sn-glycerol 3-phosphate.

    PubMed Central

    Leifer, Z; Engel, R; Tropp, B E

    1977-01-01

    3,4-Dihydroxybutyl-1-phosphonate (DHBP), an analogue of glycerol 3-phosphate, is actively transported by the sn-glycerol 3-phosphate transport system of Escherichia coli strain 8. The Km for the transport of DHBP is 200 microM. PMID:400804

  9. 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)...

  10. 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)...

  11. 40 CFR 721.6075 - Phosphonic acid, 1,1-methylenebis-tetrakis(1-methylethyl) ester.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ...-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)...

  12. 40 CFR 721.6075 - Phosphonic acid, 1,1-methylenebis-tetrakis(1-methylethyl) ester.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ...-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)...

  13. 40 CFR 721.6075 - Phosphonic acid, 1,1-methylenebis-tetrakis(1-methylethyl) ester.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ...-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)...

  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. 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...

  16. 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...

  17. Synthesis of l-lyxo-phytosphingosine and its 1-phosphonate analogue using a threitol acetal synthon.

    PubMed

    Lu, Xuequan; Byun, Hoe-Sup; Bittman, Robert

    2004-08-06

    The first synthesis of an isosteric phosphonate analogue of the aminotriol lipid phytosphingosine (3), together with an improved synthesis of (2S,3S,4S)-phytosphingosine (2), are described. A key intermediate is 3-pentylidene acetal 9, which was prepared in two steps from dimethyl 2,3-O-benzylidene-d-tartrate (7).

  18. Kinetic resolution of racemic carboxylic acids through asymmetric protolactonization promoted by chiral phosphonous acid diester.

    PubMed

    Sakuma, Masayuki; Sakakura, Akira; Ishihara, Kazuaki

    2013-06-07

    Chiral phosphonium salts induce the kinetic resolution of racemic α-substituted unsaturated carboxylic acids through asymmetric protolactonization. Both the lactones and the recovered carboxylic acids are obtained with high enantioselectivities and high S (= kfast/kslow) values. Asymmetric protolactonization also leads to the desymmetrization of achiral carboxylic acids. Notably, chiral phosphonous acid diester not only induced the enantioselectivity but also promoted protolactonization.

  19. Fluorescent carboxylic and phosphonic acids: comparative photophysics from solution to organic nanoparticles.

    PubMed

    Faucon, Adrien; Lenk, Romaric; Hémez, Julie; Gautron, Eric; Jacquemin, Denis; Le Questel, Jean-Yves; Graton, Jérôme; Brosseau, Arnaud; Ishow, Eléna

    2013-08-14

    Phosphonic and carboxylic fluorescent nanoparticles have been fabricated by direct reprecipitation in water. Their fluorescence properties strongly differ from those of the corresponding esters where strong H-bonding formation is prohibited. Comparative experiments between the two acid derivatives, differing only in their acid functions while keeping the same alkyl chain, have evidenced the peculiar behavior of the phosphonic acid derivative compared to its carboxylic analog. A dramatic emission quenching for the phosphonic acid in aprotic toluene could be observed while a fivefold increase in the fluorescence signal was observed for molecules assembled as nanoparticles. Such properties have been attributed on the theoretical basis to the formation of folded conformers in solution, leading to deactivation of the radiative excited state through intramolecular H-bonding. These studies evidence for the first time through time-resolved fluorescence measurements the stronger H-donating character of phosphonic acids compared to the carboxylic ones, and provide information on the degree of structural heterogeneity within the nanoparticles. They should pave the way for the rational fabrication of chelating acid fluorophores, able to complex metal oxides to yield stiff hybrid magnetofluorescent nanoparticles which are attracting considerable attention in the growing fields of bimodal imaging and vectorization applications.

  20. 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 (...

  1. Synthesis and characterization of phosphonates from methyl linoleate and vegetable oils

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Phosphonates were synthesized on a medium scale (~200 g) from three lipids: methyl linoleate (MeLin), high-oleic sunflower oil (HOSO) and soybean oil (SBO), and three dialkyl phosphites: methyl, ethyl and n-butyl, using a radical initiator. A staged addition of the lipid and the initiator to the dia...

  2. Synthesis and characterization of phosphonates from methyl linoleate and vegetable oils

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Phosphonates were synthesized on a medium scale (~200 g) from three lipids–methyl linoleate (MeLin), high-oleic sunflower oil (HOSO) and soybean oil (SBO), and three dialkyl phosphites–methyl, ethyl and n-butyl, using a radical initiator. A staged addition of the lipid and the initiator was used to ...

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

    PubMed

    Ma, Tian-Yi; Yuan, Zhong-Yong

    2011-10-17

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

  4. 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.

  5. 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.

  6. Nucleobase and nucleoside transport and integration into plant metabolism.

    PubMed

    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.

  7. Improving nucleoside diphosphate kinase for antiviral nucleotide analogs activation.

    PubMed

    Gallois-Montbrun, Sarah; Schneider, Benoit; Chen, Yuxing; Giacomoni-Fernandes, Veronique; Mulard, Laurence; Morera, Solange; Janin, Joel; Deville-Bonne, Dominique; Veron, Michel

    2002-10-18

    Antiviral nucleoside analog therapies rely on their incorporation by viral DNA polymerases/reverse transcriptase leading to chain termination. The analogs (3'-deoxy-3'-azidothymidine (AZT), 2',3'-didehydro-2',3'-dideoxythymidine (d4T), and other dideoxynucleosides) are sequentially converted into triphosphate by cellular kinases of the nucleoside salvage pathway and are often poor substrates of these enzymes. Nucleoside diphosphate (NDP) kinase phosphorylates the diphosphate derivatives of the analogs with an efficiency some 10(4) lower than for its natural substrates. Kinetic and structural studies of Dictyostelium and human NDP kinases show that the sugar 3'-OH, absent from all antiviral analogs, is required for catalysis. To improve the catalytic efficiency of NDP kinase on the analogs, we engineered several mutants with a protein OH group replacing the sugar 3'-OH. The substitution of Asn-115 in Ser and Leu-55 in His results in an NDP kinase mutant with an enhanced ability to phosphorylate antiviral derivatives. Transfection of the mutant enzyme in Escherichia coli results in an increased sensitivity to AZT. An x-ray structure at 2.15-A resolution of the Dictyostelium enzyme bearing the serine substitution in complex with the R(p)-alpha-borano-triphosphate derivative of AZT shows that the enhanced activity reflects an improved geometry of binding and a favorable interaction of the 3'-azido group with the engineered serine.

  8. Broad specificity of human phosphoglycerate kinase for antiviral nucleoside analogs.

    PubMed

    Gallois-Montbrun, Sarah; Faraj, Abdesslem; Seclaman, Edward; Sommadossi, Jean-Pierre; Deville-Bonne, Dominique; Véron, Michel

    2004-11-01

    Nucleoside analogs used in antiviral therapies need to be phosphorylated to their tri-phospho counterparts in order to be active on their cellular target. Human phosphoglycerate kinase (hPGK) was recently reported to participate in the last step of phosphorylation of cytidine L-nucleotide derivatives [Krishnan PGE, Lam W, Dutschman GE, Grill SP, Cheng YC. Novel role of 3-phosphoglycerate kinase, a glycolytic enzyme, in the activation of L-nucleoside analogs, a new class of anticancer and antiviral agents. J Biol Chem 2003;278:36726-32]. In the present work, we extended the enzymatic study of human PGK specificity to purine and pyrimidine nucleotide derivatives in both D- and L-configuration. Human PGK demonstrated catalytic efficiencies in the 10(4)-10(5)M(-1)s(-1) range for purine ribo-, deoxyribo- and dideoxyribonucleotide derivatives, either in D- or L-configuration. In contrast, it was poorly active with natural pyrimidine D-nucleotides (less than 10(3)M(-1)s(-1)). Pyrimidine L-enantiomers, which are promising therapeutic analogs against B hepatitis, were 2-25 times better substrates than their D-counterparts. The broad specificity of substrate of human PGK suggests that this enzyme may be involved in the cellular activation of several antiviral nucleoside analogs including dideoxyinosine, acyclovir, L-2'-deoxycytosine and L-2'-deoxythymidine.

  9. An adenosine nucleoside analogue NITD008 inhibits EV71 proliferation.

    PubMed

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

    2014-12-01

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

  10. 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

  11. 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

  12. 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.

  13. 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.

  14. Synergistic effects of acyclic retinoid and OSI-461 on growth inhibition and gene expression in human hepatoma cells.

    PubMed

    Shimizu, Masahito; Suzui, Masumi; Deguchi, Atsuko; Lim, Jin T E; Xiao, Danhua; Hayes, Julia H; Papadopoulos, Kyriakos P; Weinstein, I Bernard

    2004-10-01

    Hepatoma is one of the most frequently occurring cancers worldwide. However, effective chemotherapeutic agents for this disease have not been developed. Acyclic retinoid, a novel synthetic retinoid, can reduce the incidence of postsurgical recurrence of hepatoma and improve the survival rate. OSI-461, a potent derivative of exisulind, can increase intracellular levels of cyclic GMP, which leads to activation of protein kinase G and induction of apoptosis in cancer cells. In the present study, we examined the combined effects of acyclic retinoid plus OSI-461 in the HepG2 human hepatoma cell line. We found that the combination of as little as 1.0 micromol/L acyclic retinoid and 0.01 micromol/L OSI-461 exerted synergistic inhibition of the growth of HepG2 cells. Combined treatment with low concentrations of these two agents also acted synergistically to induce apoptosis in HepG2 cells through induction of Bax and Apaf-1, reduction of Bcl-2 and Bcl-xL, and activation of caspase-3, -8, and -9. OSI-461 enhanced the G0-G1 arrest caused by acyclic retinoid, and the combination of these agents caused a synergistic decrease in the levels of expression of cyclin D1 protein and mRNA, inhibited cyclin D1 promoter activity, decreased the level of hyperphosphorylated forms of the Rb protein, induced increased cellular levels of the p21(CIP1) protein and mRNA, and stimulated p21(CIP1) promoter activity. Moreover, OSI-461 enhanced the ability of acyclic retinoid to induce increased cellular levels of retinoic acid receptor beta and to stimulate retinoic acid response element-chloramphenicol acetyltransferase activity. A hypothetical model involving concerted effects on p21(CIP1) and retinoic acid receptor beta expression is proposed to explain these synergistic effects. Our results suggest that the combination of acyclic retinoid plus OSI-461 might be an effective regimen for the chemoprevention and chemotherapy of human hepatoma and possibly other malignancies.

  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. The preparation and intra- and intermolecular addition reactions of acyclic N-acylimines: application to the synthesis of (+/-)-sertraline.

    PubMed

    DeNinno, M P; Eller, C; Etienne, J B

    2001-10-19

    Intramolecular endo-cyclization reactions of N-acyliminium ions have seen wide application for the synthesis of heterocyclic compounds. The corresponding exocyclic variant, which would provide 1-aminotetralin derivatives, for example, has little precedent. We have discovered that acyclic N-acylcarbamates can be readily reduced to the corresponding N-acylhemiaminal derivatives in high yield using DIBAL as the reducing agent. These intermediates are remarkably stable and, if desired, can be purified and stored. The acyclic N-acylhemiaminals undergo both intra- and intermolecular nucleophilic addition reactions mediated by strong Lewis acids, such as TiCl(4). Diastereoselectivity, induced either by a substituent on the newly formed ring, or by utilizing a chiral ester on the carbamic acid, was disappointingly low. This methodology was successfully applied to the synthesis of the racemic form of the marketed antidepressant sertraline.

  17. 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).

  18. Enzymatic study on AtCCD4 and AtCCD7 and their potential to form acyclic regulatory metabolites

    PubMed Central

    Bruno, Mark; Koschmieder, Julian; Wuest, Florian; Schaub, Patrick; Fehling-Kaschek, Mirjam; Timmer, Jens; Beyer, Peter; Al-Babili, Salim

    2016-01-01

    The Arabidopsis carotenoid cleavage dioxygenase 4 (AtCCD4) is a negative regulator of the carotenoid content of seeds and has recently been suggested as a candidate for the generation of retrograde signals that are thought to derive from the cleavage of poly-cis-configured carotene desaturation intermediates. In this work, we investigated the activity of AtCCD4 in vitro and used dynamic modeling to determine its substrate preference. Our results document strict regional specificity for cleavage at the C9–C10 double bond in carotenoids and apocarotenoids, with preference for carotenoid substrates and an obstructing effect on hydroxyl functions, and demonstrate the specificity for all-trans-configured carotenes and xanthophylls. AtCCD4 cleaved substrates with at least one ionone ring and did not convert acyclic carotene desaturation intermediates, independent of their isomeric states. These results do not support a direct involvement of AtCCD4 in generating the supposed regulatory metabolites. In contrast, the strigolactone biosynthetic enzyme AtCCD7 converted 9-cis-configured acyclic carotenes, such as 9-cis-ζ-carotene, 9'-cis-neurosporene, and 9-cis-lycopene, yielding 9-cis-configured products and indicating that AtCCD7, rather than AtCCD4, is the candidate for forming acyclic retrograde signals. PMID:27811075

  19. Mesoporous cerium phosphonate nanostructured hybrid spheres as label-free Hg²⁺ fluorescent probes.

    PubMed

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

    2014-09-24

    Porous phosphonate-based organic-inorganic hybrid materials have been shown to have novel and amazing physicochemical properties due to the integration of superiorities from both inorganic components and organic moieties. Herein, mesoporous cerium phosphonate nanostructured hybrid spheres are prepared with the assistance of cationic surfactant cetyltrimethylammonium bromide while using ethylene diamine tetra(methylene phosphonic acid) as the coupling molecule. The resulting hybrid is constructed from the cerium phosphonate nanoparticles, accompanied by high specific surface area of 455 m(2) g(-1). The uniform incorporation of rare-earth element cerium and organophosphonic functionalities endows mesoporous cerium phosphonate with excellent fluorescence properties for the development of an optical sensor for selective Hg(2+) detection on the basis of the fluorescence-quenching mechanism. The signal response of mesoporous cerium phosphonate against the Hg(2+) concentration is linear over the range from 0.05 to 1.5 μmol L(-1), giving a limit of detection of 16 nmol L(-1) (at a signal-to-noise ratio of 3). Most of the common physiologically relevant cations and anions did not interfere with the detection of Hg(2+). This label-free system provides a promising platform for further use in bioimaging and biomedical fields.

  20. 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

  1. Invited commentary: the perils of birth weight--a lesson from directed acyclic graphs.

    PubMed

    Wilcox, Allen J

    2006-12-01

    The strong association of birth weight with infant mortality is complicated by a paradoxical finding: Small babies in high-risk populations usually have lower risk than small babies in low-risk populations. In this issue of the Journal, Hernández-Díaz et al. (Am J Epidemiol 2006;164:1115-20) address this "birth weight paradox" using directed acyclic graphs (DAGs). They conclude that the paradox is the result of bias created by adjustment for a factor (birth weight) that is affected by the exposure of interest and at the same time shares causes with the outcome (mortality). While this bias has been discussed before, the DAGs presented by Hernández-Díaz et al. provide more firmly grounded criticism. The DAGs demonstrate (as do many other examples) that seemingly reasonable adjustments can distort epidemiologic results. In this commentary, the birth weight paradox is shown to be an illustration of Simpson's Paradox. It is possible for a factor to be protective within every stratum of a variable and yet be damaging overall. Questions remain as to the causal role of birth weight.

  2. Polarizable empirical force field for acyclic polyalcohols based on the classical Drude oscillator.

    PubMed

    He, Xibing; Lopes, Pedro E M; Mackerell, Alexander D

    2013-10-01

    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 resulting 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.

  3. 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.

  4. A multiple testing method for hypotheses structured in a directed acyclic graph.

    PubMed

    Meijer, Rosa J; Goeman, Jelle J

    2015-01-01

    We present a novel multiple testing method for testing null hypotheses that are structured in a directed acyclic graph (DAG). The method is a top-down method that strongly controls the familywise error rate and can be seen as a generalization of Meinshausen's procedure for tree-structured hypotheses. Just as Meinshausen's procedure, our proposed method can be used to test for variable importance, only the corresponding variable clusters can be chosen more freely, because the method allows for multiple parent nodes and partially overlapping hypotheses. An important application of our method is in gene set analysis, in which one often wants to test multiple gene sets as well as individual genes for their association with a clinical outcome. By considering the genes and gene sets as nodes in a DAG, our method enables us to test both for significant gene sets as well as for significant individual genes within the same multiple testing procedure. The method will be illustrated by testing Gene Ontology terms for evidence of differential expression in a survival setting and is implemented in the R package cherry.

  5. Robust causal inference using directed acyclic graphs: the R package 'dagitty'.

    PubMed

    Textor, Johannes; van der Zander, Benito; Gilthorpe, Mark S; Liśkiewicz, Maciej; Ellison, George T H

    2017-01-15

    Directed acyclic graphs (DAGs), which offer systematic representations of causal relationships, have become an established framework for the analysis of causal inference in epidemiology, often being used to determine covariate adjustment sets for minimizing confounding bias. DAGitty is a popular web application for drawing and analysing DAGs. Here we introduce the R package 'dagitty', which provides access to all of the capabilities of the DAGitty web application within the R platform for statistical computing, and also offers several new functions. We describe how the R package 'dagitty' can be used to: evaluate whether a DAG is consistent with the dataset it is intended to represent; enumerate 'statistically equivalent' but causally different DAGs; and identify exposure-outcome adjustment sets that are valid for causally different but statistically equivalent DAGs. This functionality enables epidemiologists to detect causal misspecifications in DAGs and make robust inferences that remain valid for a range of different DAGs. The R package 'dagitty' is available through the comprehensive R archive network (CRAN) at [https://cran.r-project.org/web/packages/dagitty/]. The source code is available on github at [https://github.com/jtextor/dagitty]. The web application 'DAGitty' is free software, licensed under the GNU general public licence (GPL) version 2 and is available at [http://dagitty.net/].

  6. 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.

  7. 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.

  8. Terahertz vibrations of crystalline acyclic and cyclic diglycine: benchmarks for London force correction models.

    PubMed

    Juliano, Thomas R; Korter, Timothy M

    2013-10-10

    Terahertz spectroscopy provides direct information concerning weak intermolecular forces in crystalline molecular solids and therefore acts as an excellent method for calibrating and evaluating computational models for noncovalent interactions. In this study, the low-frequency vibrations of two dipeptides were compared, acyclic diglycine and cyclic diglycine, as benchmark systems for gauging the performance of semiempirical London force correction approaches. The diglycine samples were investigated using pulsed terahertz spectroscopy from 10 to 100 cm(-1) and then analyzed using solid-state density functional theory (DFT) augmented with existing London force corrections, as well as a new parametrization (DFT-DX) based on known experimental values. The two diglycine molecules provide a useful test for the applied models given their similarities, but more importantly the differences in the intermolecular forces displayed by each. It was found that all of the considered London force correction models were able to generate diglycine crystal structures of similar accuracy, but considerable variation occurred in their abilities to predict terahertz frequency vibrations. The DFT-DX parametrization was particularly successful in this investigation and shows promise for the improved analysis of low-frequency spectra.

  9. "Toward a clearer definition of confounding" revisited with directed acyclic graphs.

    PubMed

    Howards, Penelope P; Schisterman, Enrique F; Poole, Charles; Kaufman, Jay S; Weinberg, Clarice R

    2012-09-15

    In a 1993 paper (Am J Epidemiol. 1993;137(1):1-8), Weinberg considered whether a variable that is associated with the outcome and is affected by exposure but is not an intermediate variable between exposure and outcome should be considered a confounder in etiologic studies. As an example, she examined the common practice of adjusting for history of spontaneous abortion when estimating the effect of an exposure on the risk of spontaneous abortion. She showed algebraically that such an adjustment could substantially bias the results even though history of spontaneous abortion would meet some definitions of a confounder. Directed acyclic graphs (DAGs) were introduced into epidemiology several years later as a tool with which to identify confounders. The authors now revisit Weinberg's paper using DAGs to represent scenarios that arise from her original assumptions. DAG theory is consistent with Weinberg's finding that adjusting for history of spontaneous abortion introduces bias in her original scenario. In the authors' examples, treating history of spontaneous abortion as a confounder introduces bias if it is a descendant of the exposure and is associated with the outcome conditional on exposure or is a child of a collider on a relevant undirected path. Thoughtful DAG analyses require clear research questions but are easily modified for examining different causal assumptions that may affect confounder assessment.

  10. 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.

  11. 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.

  12. Purines 2010: Adenine Nucleosides and Nucleotides in Biomedicine.

    PubMed

    Sereda, Michal J

    2010-08-01

    The Purines 2010: Adenine Nucleosides and Nucleotides in Biomedicine meeting, held in Tarragona, Spain, included topics covering new findings in the field of purinergic signaling and the development of purine-based drugs. This conference report highlights selected presentations on developments in purinerigic signaling, medicinal chemistry, the therapeutic potential of purine-based drugs, and the role of purines and adenosine receptors in neurodegenerative disorders, sickle cell disease, bone homeostasis, pulmonary fibrosis and pain. Investigational drugs discussed include CF-101 (Can-Fite BioPharma Ltd/NIH/Kwang Dong Pharmaceutical Co Ltd/Seikagaku Corp) and denufosol tetrasodium (Cystic Fibrosis Foundation Therapeutics Inc/Inspire Pharmaceuticals Inc).

  13. 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.

  14. Identification of a novel family of nucleosides that specifically inhibit HIV-1 reverse transcriptase.

    PubMed

    Chamorro, C; Lobatón, E; Bonache, M C; De Clercq, E; Balzarini, J; Velázquez, S; San-Félix, A; Camarasa, M J

    2001-12-03

    N-3-Benzyloxycarbonylmethyl- and N-3-carboxymethyl-TBDMS-substituted nucleosides were synthesized and evaluated for activity against HIV replication. It was found that the N-3-carboxymethyl-TBDMS-substituted nucleosides were specific inhibitors of HIV-1 replication. They should be considered as members of a novel and original class of NNRTIs.

  15. 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…

  16. Nucleoside H-boranophosphonates: a new class of boron-containing nucleotide analogues.

    PubMed

    Higashida, Renpei; Oka, Natsuhisa; Kawanaka, Toshihide; Wada, Takeshi

    2009-05-14

    A study on the synthesis of nucleoside H-boranophosphonates, a new class of nucleotide analogues having a P-->BH(3) and a P-H group, via condensation of the corresponding nucleosides with H-boranophosphonate derivatives is described.

  17. Biosynthesis of murein lipoprotein in Escherichia coli: effects of 3,4-dihydroxybutyl-1-phosphonate.

    PubMed Central

    Chattopadhyay, P K; Engel, R; Tropp, B E; Wu, H C

    1979-01-01

    The effects of 3,4-dihydroxybutyl-1-phosphonate, a four-carbon analog of sn-glycerol 3-phosphate, on the biosynthesis of the glyceryl moiety in murein lipoprotein of Escherichia coli were studied. The compound at a concentration of 55 microM strong inhibits in the incorporation of [2-3H]glycerol radioactivity into lipoprotein by virtue of its inhibition of the synthesis of phosphatidylglycerol. On the other hand, the incorporation of prelabeled [2-3H]glycerol radioactivity into lipoprotein was only partially inhbited by 3,4-dihydroxybutyl-1-phosphonate even at a much higher concentration (1 mM). These data were consistent with the postulated pathway for the biosynthesis of the lipid moiety in lipoportein: cysteine-lipoprotein + phosphatidylglycerol leads to glycerylcystein-lipoprotein + phosphatidic acid. PMID:378946

  18. Catalytic asymmetric synthesis of {alpha}-amino phosphonates using lanthanoid-potassium-BINOL complexes

    SciTech Connect

    Sasai, Hiroaki; Arai, Shigeru; Shibasaki, Masakatsu

    1995-10-20

    {alpha}-Amino phosphonic acids 3 are interesting compounds in the design of enzyme inhibitors. The concept of mimicking tetrahedral transition states of enzyme-medicated peptide bond hydrolysis previously led to the successful design and synthesis of phosphonamide-containing peptides as a promising new class of proteinase inhibitors. It is not surprising that the absolute configuration of the {alpha}-carbon strongly influences the biological properties of 3. Several methods for the synthesis of optically active {alpha}-aminophosphonic acids have been published. The authors report here the first example of a catalytic asymmetric hydrophosphonylation to imines using lanthanoid-potassium-BINOL heterobimetallic complexes (LnPB, Ln = lanthanoid metal), which gives optically active {alpha}-amino phosphonates in modest to high enantiometric excess. 17 refs., 1 tab.

  19. 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.

  20. Physico-chemical studies and emulsifying properties of N-propyl-N-methylene phosphonic chitosan.

    PubMed

    Albertengo, Liliana; Farenzena, Sonia; Debbaudt, Adriana; Zuñiga, Adriana; Schulz, Pablo; Rodriguez, Maria Susana

    2013-02-15

    Chitosan is a modified, natural carbohydrate polymer derived by deacetylation of chitin. Due to the presence of two functional groups can undergo many chemical modifications. In a previous work we described the synthetic strategy and characterization of a novel soluble derivative: N-propyl-N-methylene phosphonic chitosan (PNMPC). In the study of some physicochemical properties, results showed that this modified chitosan aggregates in several steps when the concentration is increased. By addition of NaOH the initially coiled molecules stretch exposing more phosphonic acid groups to neutralization and finally give a cooperative reaction with OH((). PNMPC has emulsifying properties and gives O/W emulsions with quasi-monodisperse small droplets. Emulsions with 0.18% PNMPC and 30:70 o:w ratio exhibited the best emulsifying properties within the test range. This emulsion ratio showed high stability to long time storage and several successive freeze/thaw and heating/cooling cycles.

  1. Binding of phosphinate and phosphonate inhibitors to aspartic proteases: a first-principles study.

    PubMed

    Vidossich, Pietro; Carloni, Paolo

    2006-01-26

    Phosphinate and phosphonate derivatives are potent inhibitors of aspartic proteases (APs). The affinity for the enzyme might be caused by the presence of low barrier hydrogen bonds between the ligand and the catalytic Asp dyad in the cleavage site. We have used density functional theory calculations along with hybrid quantum mechanics/molecular mechanics Car-Parrinello molecular dynamics simulations to investigate the hydrogen-bonding pattern at the binding site of the complexes of human immunodeficiency virus type-1 AP and the eukaryotic endothiapepsin and penicillopepsin. Our calculations are in fair agreement with the NMR data available for endothiapepsin (Coates et al. J. Mol. Biol. 2002, 318, 1405-1415) and show that the most stable active site configuration is the diprotonated, negatively charged form. In the viral complex both protons are located at the catalytic Asp dyad, while in the eukaryotic complexes the proton shared by the closest oxygen atoms is located at the phosphinic/phosphonic group.

  2. Environmental risk assessment of phosphonates, used in domestic laundry and cleaning agents in The Netherlands.

    PubMed

    Jaworska, Joanna; Van Genderen-Takken, Helen; Hanstveit, Arnbjorn; van de Plassche, Erik; Feijtel, Tom

    2002-05-01

    In the long-term cooperative project Voluntary Plan of Action (1990) between the Dutch Soap and Detergent Association (NVZ) and the Dutch Ministry of Housing, Spatial Planning and the Environment (VROM) environmental risk assessments of several main components of laundry cleaning formulations were completed. As a part of that project the environmental risk assessment of HEDP, ATMP, EDTMP and DTPMP phosphonates used in detergent applications has been carried out according to the EU Technical Guidance Document for Environmental Risk Assessment for New and Existing Chemicals. All PEC/PNEC ratios were well below 1. Results of this assessment based on the total industry volumes from 1995 and 1998 indicate that the environmental risk of these phosphonates is low in The Netherlands with properly functioning sewage treatment plants.

  3. A convenient synthesis of a novel nucleoside analogue: 4-(alpha-diformyl-methyl)-1-(beta-D-ribofuranosyl)-2-pyrimidinone

    NASA Technical Reports Server (NTRS)

    Gao, K.; Orgel, L. E.; Bada, J. L. (Principal Investigator)

    2000-01-01

    The nucleoside analogue 4-(alpha-diformyl-methyl)-1-(beta-D-ribofuranosyl)-2-pyrimidinone (5) was prepared from the corresponding 4-methyl pyrimidinone nucleoside by means of the Vilsmeier reaction. The unprotected nucleoside can be phosphorylated directly with phosphorus oxychloride in triethyl phosphate.

  4. Rigid 5'-6-locked phenanthroline-derived nucleosides chelated to ruthenium and europium ions.

    PubMed

    Gislason, Kristmann; Sigurdsson, Snorri Th

    2013-01-01

    We describe complexes of ruthenium and europium with rigid, 5'-6-locked 1,10-phenanthroline-containing nucleosides. Both nucleosides were synthesized from condensation of 5-amino-2'-deoxycytidine with the corresponding diketone. The ruthenium nucleoside displayed fluorescence characteristic of polypyridine ruthenium complexes with a maximum at 616 nm and a quantum yield of 0.011. Binding of europium to the 1,10-phenanthroline-2,9-diacid moiety of the lanthanide binding nucleoside showed formation of a 1:1 complex with emission at 570-630 nm, whose emission was enhanced by addition of two phenanthroline ligands. The lanthanide-binding nucleoside was incorporated into DNA oligonucleotides and shown to selectively bind one equivalent of europium ions.

  5. 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

  6. 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.

  7. Synthesis of phosphonic analogues of carnitine and gamma-amino-beta-hydroxybutyric acid.

    PubMed

    Tadeusiak, Elzbieta J

    2004-12-01

    The involvement of carnitine and gamma-amino-beta-hydroxybutyric acid in the biology of mammalian cells, the physiology of the human body, and some important aspects of medicinal treatment has induced many research groups to develop their pharmacologically potent analogues. Among them are the very important phosphonic analogues: phosphocarnitine and gamma-amino-beta-hydroxypropylphosphonic acid. This mini-review describes the various methodologies used for the synthesis of these compounds.

  8. 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...

  9. In situ chemical functionalization of gallium nitride with phosphonic acid derivatives during etching.

    PubMed

    Wilkins, Stewart J; Greenough, Michelle; Arellano, Consuelo; Paskova, Tania; Ivanisevic, Albena

    2014-03-04

    In situ functionalization of polar (c plane) and nonpolar (a plane) gallium nitride (GaN) was performed by adding (3-bromopropyl) phosphonic acid or propyl phosphonic acid to a phosphoric acid etch. The target was to modulate the emission properties and oxide formation of GaN, which was explored through surface characterization with atomic force microscopy, X-ray photoelectron spectroscopy, photoluminescence (PL), inductively coupled plasma-mass spectrometry, and water contact angle. The use of (3-bromopropyl) phosphonic acid and propyl phosphonic acid in phosphoric acid demonstrated lower amounts of gallium oxide formation and greater hydrophobicity for both sample sets, while also improving PL emission of polar GaN samples. In addition to crystal orientation, growth-related factors such as defect density in bulk GaN versus thin GaN films residing on sapphire substrates were investigated as well as their responses to in situ functionalization. Thin nonpolar GaN layers were the most sensitive to etching treatments due in part to higher defect densities (stacking faults and threading dislocations), which accounts for large surface depressions. High-quality GaN (both free-standing bulk polar and bulk nonpolar) demonstrated increased sensitivity to oxide formation. Room-temperature PL stands out as an excellent technique to identify nonradiative recombination as observed in the spectra of heteroepitaxially grown GaN samples. The chemical methods applied to tune optical and physical properties of GaN provide a quantitative framework for future novel chemical and biochemical sensor development.

  10. 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.

  11. Low adhesion, non-wetting phosphonate self-assembled monolayer films formed on copper oxide surfaces.

    PubMed

    Hoque, E; DeRose, J A; Bhushan, B; Hipps, K W

    2009-07-01

    Self-assembled monolayer (SAM) films have been formed on oxidized copper (Cu) substrates by reaction with 1H,1H,2H,2H-perfluorodecylphosphonic acid (PFDP), octadecylphosphonic acid (ODP), decylphosphonic acid (DP), and octylphosphonic acid (OP) and then investigated by X-ray photoelectron spectroscopy (XPS), contact angle measurement (CAM), and atomic force microscopy (AFM). The presence of alkyl phosphonate molecules, PFDP, ODP, DP, and OP, on Cu were confirmed by CAM and XPS analysis. No alkyl phosphonate molecules were seen by XPS on unmodified Cu as a control. The PFDP/Cu and ODP/Cu SAMs were found to be very hydrophobic having water sessile drop static contact angles of more than 140 degrees , while DP/Cu and OP/Cu have contact angles of 119 degrees and 76 degrees , respectively. PFDP/Cu, ODP/Cu, DP/Cu, and OP/Cu SAMs were studied by friction force microscopy, a derivative of AFM, to better understand their micro/nanotribological properties. PFDP/Cu, ODP/Cu, and DP/Cu had comparable adhesive force, which is much lower than that for unmodified Cu. ODP/Cu had the lowest friction coefficient followed by PFDP/Cu, DP/Cu, and OP/Cu while unmodified Cu had the highest. XPS data gives some indication that a bidentate bond forms between the alkyl phosphonate molecules and the oxidized Cu surface. Hydrophobic phosphonate SAMs could be useful as corrosion inhibitors in micro/nanoelectronic devices and/or as promoters for anti-wetting, low adhesion surfaces.

  12. Two isomeric lead(II) carboxylate-phosphonates: syntheses, crystal structures and characterizations

    NASA Astrophysics Data System (ADS)

    Lei, Chong; Mao, Jiang-Gao; Sun, Yan-Qiong

    2004-07-01

    Two isomeric layered lead(II) carboxylate-phosphonates of N-(phosphonomethyl)- N-methyl glycine ([MeN(CH 2CO 2H)(CH 2PO 3H 2)]=H 3L), namely, monoclinic Pb 3L 2·H 2O 1 and triclinic Pb 3L 2·H 2O 2, have been synthesized and structurally determined. Compound 1 synthesized by hydrothermal reaction at 150°C is monoclinic, space group C2/ c with a=19.9872(6), b=11.9333(1) and c=15.8399(4) Å, β=110.432(3)°, V=3540.3(1) Å 3, and Z=8. The structure of compound 1 features a <400> layer in which the lead(II) ions are bridged by both phosphonate and carboxylate groups. The lattice water molecules are located between the layers, forming hydrogen bonds with the non-coordinated carboxylate oxygen atoms. Compound 2 with a same empirical formula as compound 1 was synthesized by hydrothermal reaction at 170°C. It has a different layer structure from that of compound 1 due to the adoption of a different coordination mode for the ligand. It crystallizes in the triclinic system, space group P 1¯ with cell parameters of a=7.1370(6), b=11.522(1), c=11.950(1) Å, α=110.280(2), β=91.625(2), γ=95.614(2)°, V=915.3(1) Å 3 and Z=2. The structure of compound 2 features a <020> metal carboxylate-phosphonate double layer built from 1D lead(II) carboxylate chains interconnected with 1D lead(II) phosphonate double chains. XRD powder patterns of compounds 1 and 2 indicate that each compound exists as a single phase.

  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. Synthesis and properties of ApA analogues with shortened phosphonate internucleotide linkage.

    PubMed

    Králíková, Sárka; Buděšínský, Miloš; Barvík, Ivan; Masojídková, Milena; Točík, Zdeněk; Rosenberg, Ivan

    2011-01-01

    A complete series of the 2 '-5 ' and 3 '-5 ' regioisomeric types of r(ApA) and 2 '-d(ApA) analogues with the α-hydroxy-phosphonate C3 '-O-P-CH(OH)-C4 ″ internucleotide linkage, isopolar but non-isosteric with the phosphodiester one, were synthesized and their hybridization properties with polyU studied. Due to the chirality on the 5 '-carbon atom of the modified internucleotide linkage bearing phosphorus and hydroxy moieties, each regioisomeric type of ApA dimer is split into epimeric pairs. To examine the role of the 5 '-hydroxyl of the α-hydroxy-phosphonate moiety during hybridization, the appropriate r(ApA) analogues with 3 '(2 ')-O-P-CH(2)-C4 ″ linkage lacking the 5 '-hydroxyl were synthesized. Nuclear magnetic resonance (NMR) spectroscopy study on the conformation of the modified sugar-phosphate backbone, along with the hybridization measurements, revealed remarkable differences in the stability of complexes with polyU, depending on the 5 '-carbon atom configuration. Potential usefulness of the α-hydroxy-phosphonate linkage in modified oligoribonucleotides is discussed.

  16. Covalent attachment of diamondoid phosphonic acid dichlorides to tungsten oxide surfaces.

    PubMed

    Li, Fei Hua; Fabbri, Jason D; Yurchenko, Raisa I; Mileshkin, Alexander N; Hohman, J Nathan; Yan, Hao; Yuan, Hongyuan; Tran, Ich C; Willey, Trevor M; Bagge-Hansen, Michael; Dahl, Jeremy E P; Carlson, Robert M K; Fokin, Andrey A; Schreiner, Peter R; Shen, Zhi-Xun; Melosh, Nicolas A

    2013-08-06

    Diamondoids (nanometer-sized diamond-like hydrocarbons) are a novel class of carbon nanomaterials that exhibit negative electron affinity (NEA) and strong electron-phonon scattering. Surface-bound diamondoid monolayers exhibit monochromatic photoemission, a unique property that makes them ideal electron sources for electron-beam lithography and high-resolution electron microscopy. However, these applications are limited by the stability of the chemical bonding of diamondoids on surfaces. Here we demonstrate the stable covalent attachment of diamantane phosphonic dichloride on tungsten/tungsten oxide surfaces. X-ray photoelectron spectroscopy (XPS) and Fourier-transform infrared (FTIR) spectroscopy revealed that diamondoid-functionalized tungsten oxide films were stable up to 300-350 °C, a substantial improvement over conventional diamondoid thiolate monolayers on gold, which dissociate at 100-200 °C. Extreme ultraviolet (EUV) light stimulated photoemission from these diamondoid phosphonate monolayers exhibited a characteristic monochromatic NEA peak with 0.2 eV full width at half-maximum (fwhm) at room temperature, showing that the unique monochromatization property of diamondoids remained intact after attachment. Our results demonstrate that phosphonic dichloride functionality is a promising approach for forming stable diamondoid monolayers for elevated temperature and high-current applications such as electron emission and coatings in micro/nano electromechanical systems (MEMS/NEMS).

  17. 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.

  18. Resolving Ultrafast Photoinduced Deactivations in Water-solvated Pyrimidine Nucleosides.

    PubMed

    Pepino, Ana J; Segarra-Martí, Javier; Nenov, Artur; Improta, Roberto; Garavelli, Marco

    2017-03-27

    For the first time, ultrafast deactivations of photo-excited water-solvated pyrimidine nucleosides are mapped employing hybrid QM(CASPT2)/MM(AMBER) optimizations that account for explicit solvation, sugar effects and dynamically correlated potential energy surfaces. Low energy S1/S0 ring-puckering and ring-opening conical intersections (CIs) are suggested to drive the ballistic coherent sub-ps (<200fs) decays observed in each pyrimidine, the energetics controlling this processes correlating with the lifetimes observed. A second bright 1π2π* state, promoting excited-state population branching and leading towards a third CI with the ground state, is proposed to be involved in the slower ultrafast decay component observed in Thd/Cyd. The transient spectroscopic signals of the competitive deactivation channels are computed for the first time. A general unified scheme for ultrafast deactivations, spanning the sub-to-few ps time domain, is eventually delivered, with computed data that matches the experiments and elucidates the intrinsic photo-protection mechanism in solvated pyrimidine nucleosides.

  19. 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

  20. Prodrugs of aza nucleosides based on proton transfer reaction

    NASA Astrophysics Data System (ADS)

    Karaman, Rafik

    2010-12-01

    DFT calculation results for intramolecular proton transfer reactions in Kirby's enzyme models 1- 7 reveal that the reaction rate is quite responsive to geometric disposition, especially to distance between the two reactive centers, r GM, and the angle of attack, α (the hydrogen bonding angle). Hence, the study on the systems reported herein could provide a good basis for designing aza nucleoside prodrug systems that are less hydrophilic than their parental drugs and can be used, in different dosage forms, to release the parent drug in a controlled manner. For example, based on the calculated log EM, the cleavage process for prodrug 1ProD is predicted to be about 1010 times faster than that for prodrug 7ProD and about 104 times faster than prodrug 3ProD: rate 1ProD > rate 3ProD > rate 7ProD . Hence, the rate by which the prodrug releases the aza nucleoside drug can be determined according to the structural features of the linker (Kirby's enzyme model).

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

    PubMed

    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

    2015-10-09

    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 in 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 ribose analogue of cladribine showed activity, but was the 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, cladribine and its ribose analogue were most active.

  2. 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.

  3. 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.

  4. A layered mixed zirconium phosphate/phosphonate with exposed carboxylic and phosphonic groups: X-ray powder structure and proton conductivity properties.

    PubMed

    Donnadio, Anna; Nocchetti, Morena; Costantino, Ferdinando; Taddei, Marco; Casciola, Mario; da Silva Lisboa, Fábio; Vivani, Riccardo

    2014-12-15

    A novel mixed zirconium phosphate/phosphonate based on glyphosine, of formula Zr2(PO4)H5(L)2·H2O [L = (O3PCH2)2NCH2COO], was synthesized in mild conditions. The compound has a layered structure that was solved ab initio from laboratory PXRD data. It crystallizes in the monoclinic C2/c space group with the following cell parameters: a = 29.925(3), b = 8.4225(5), c = 9.0985(4) Å, and β = 98.474(6)°. Phosphate groups are placed inside the sheets and connect the zirconium atoms in a tetradentate fashion, while uncoordinated carboxylate and P-OH phosphonate groups are exposed on the layer surface. Due to the presence of these acidic groups, the compound showed remarkable proton conductivity properties, which were studied in a wide range of temperature and relative humidity (RH). The conductivity is strongly dependent on RH and reaches 1 × 10(-3) S cm(-1) at 140 °C and 95% RH. At this RH, the activation energy of conduction is 0.15 eV in the temperature range 80-140 °C. The similarities of this structure with related structures already reported in the literature were also discussed.

  5. 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

    2016-08-03

    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.

  6. 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.

  7. Gallium(III) complexes of NOTA-bis (phosphonate) conjugates as PET radiotracers for bone imaging.

    PubMed

    Holub, Jan; Meckel, Marian; Kubíček, Vojtěch; Rösch, Frank; Hermann, Petr

    2015-01-01

    Ligands with geminal bis(phosphonic acid) appended to 1,4,7-triazacyclonone-1,4-diacetic acid fragment through acetamide (NOTAM(BP) ) or methylenephosphinate (NO2AP(BP) ) spacers designed for (68) Ga were prepared. Ga(III) complexation is much faster for ligand with methylenephosphinate spacer than that with acetamide one, in both chemical (high reactant concentrations) and radiolabeling studies with no-carrier-added (68) Ga. For both ligands, formation of Ga(III) complex was slower than that with NOTA owing to the strong out-of-cage binding of bis(phosphonate) group. Radiolabeling was efficient and fast only above 60 °C and in a narrow acidity region (pH ~3). At higher temperature, hydrolysis of amide bond of the carboxamide-bis(phosphonate) conjugate was observed during complexation reaction leading to Ga-NOTA complex. In vitro sorption studies confirmed effective binding of the (68) Ga complexes to hydroxyapatite being comparable with that found for common bis(phosphonate) drugs such as pamindronate. Selective bone uptake was confirmed in healthy rats by biodistribution studies ex vivo and by positron emission tomography imaging in vivo. Bone uptake was very high, with SUV (standardized uptake value) of 6.19 ± 1.27 for [(68) Ga]NO2AP(BP) ) at 60 min p.i., which is superior to uptake of (68) Ga-DOTA-based bis(phosphonates) and [(18) F]NaF reported earlier (SUV of 4.63 ± 0.38 and SUV of 4.87 ± 0.32 for [(68) Ga]DO3AP(BP) and [(18) F]NaF, respectively, at 60 min p.i.). Coincidently, accumulation in soft tissue is generally low (e.g. for kidneys SUV of 0.26 ± 0.09 for [(68) Ga]NO2AP(BP) at 60 min p.i.), revealing the new (68) Ga complexes as ideal tracers for noninvasive, fast and quantitative imaging of calcified tissue and for metastatic lesions using PET or PET/CT.

  8. Purine and pyrimidine nucleosides preserve human astrocytoma cell adenylate energy charge under ischemic conditions.

    PubMed

    Balestri, Francesco; Giannecchini, Michela; Sgarrella, Francesco; Carta, Maria Caterina; Tozzi, Maria Grazia; Camici, Marcella

    2007-02-01

    The brain depends on both glycolysis and mitochondrial oxidative phosphorylation for maintenance of ATP pools. Astrocytes play an integral role in brain functions providing trophic supports and energy substrates for neurons. In this paper, we report that human astrocytoma cells (ADF) undergoing ischemic conditions may use both purine and pyrimidine nucleosides as energy source to slow down cellular damage. The cells are subjected to metabolic stress conditions by exclusion of glucose and incubation with oligomycin (an inhibitor of oxidative phosphorylation). This treatment brings about a depletion of the ATP pool, with a concomitant increase in the AMP levels, which results in a significant decrease of the adenylate energy charge. The presence of purine nucleosides in the culture medium preserves the adenylate energy charge, and improves cell viability. Besides purine nucleosides, also pyrimidine nucleosides, such as uridine and, to a lesser extent, cytidine, are able to preserve the ATP pool. The determination of lactate in the incubation medium indicates that nucleosides can preserve the ATP pool through anaerobic glycolysis, thus pointing to a relevant role of the phosphorolytic cleavage of the N-glycosidic bond of nucleosides which generates, without energy expense, the phosphorylated pentose, which through the pentose phosphate pathway and glycolysis can be converted to energetic intermediates also in the absence of oxygen. In fact, ADF cells possess both purine nucleoside phosphorylase and uridine phosphorylase activities.

  9. Cytostatic evaluations of nucleoside analogs related to unnatural base pairs for a genetic expansion system.

    PubMed

    Kimoto, Michiko; Moriyama, Kei; Yokoyama, Shigeyuki; Hirao, Ichiro

    2007-10-15

    The introduction of an unnatural base pair into DNA enables the expansion of genetic information. To apply unnatural base pairs to in vivo systems, we evaluated the cytostatic toxicity of several nucleoside analogs by an MTT assay. Several nucleoside analogs based on two types of unnatural base pairs were tested. One is a hydrogen-bonded base pair between 2-amino-6-(2-thienyl)purine (s) and pyridin-2-one (y), and the other is a hydrophobic base pair between 7-(2-thienyl)imidazo[4,5-b]pyridine (Ds) and pyrrole-2-carbaldehyde (Pa). Among the nucleoside analogs, the ribonucleoside of 6-(2-thienyl)purine possessed the highest cytostatic activity against CCRF-CEM and especially HT-1080, as well as the normal fibroblast cell line, WI-38. The other analogs, including its 2'-deoxy, 2-amino, and 1-deazapurine nucleoside derivatives, were less active against CCRF-CEM and HT-1080, and the toxicity of these nucleosides toward WI-38 was low. The nucleosides of y and Pa were inactive against CCRF-CEM, HT-1080, and WI-38. In addition, no cytostatic synergism was observed with the combination of the pairing nucleosides of s and y or Ds and Pa.

  10. Synthesis and photophysical characterisation of a fluorescent nucleoside analogue that signals the presence of an abasic site in RNA.

    PubMed

    Tanpure, Arun A; Srivatsan, Seergazhi G

    2012-11-05

    The synthesis and site-specific incorporation of an environment-sensitive fluorescent nucleoside analogue (2), based on a 5-(benzofuran-2-yl)pyrimidine core, into DNA oligonucleotides (ONs), and its photophysical properties within these ONs are described. Interestingly and unlike 2-aminopurine (a widely used nucleoside analogue probe), when incorporated into an ON and hybridised with a complementary ON, the emissive nucleoside 2 displays significantly higher emission intensity than the free nucleoside. Furthermore, photophysical characterisation shows that the fluorescence properties of the nucleoside analogue within ONs are significantly influenced by flanking bases, especially by guanosine. By utilising the responsiveness of the nucleoside to changes in base environment, a DNA ON reporter labelled with the emissive nucleoside 2 was constructed; this signalled the presence of an abasic site in a model depurinated sarcin/ricin RNA motif of a eukaryotic 28S rRNA.

  11. 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.

  12. 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.

  13. Zirconocene-assisted remote cleavage of C-C and C-O bonds: application to acyclic stereodefined metalated hydrocarbons.

    PubMed

    Bruffaerts, J; Pierrot, D; Marek, I

    2016-11-08

    The molding of molecules through remote functionalisation has increasingly become popular as it provides original and flexible synthetic alternatives to classical retrosynthetic analysis. In this Perspective article, we summarise more than a decade of studies in the specific field of remote activation of inert C-C and C-O bonds using the unique abilities of organozirconocene species mainly from our own research group. By demonstrating that these reactions represent novel and powerful entries towards acyclic stereodefined reactive organometallic species, we aim to show the vast opportunities this concept-driven methodology discovery offers.

  14. Nucleophilic displacement reactions of 5′-derivatised nucleosides in a vibration ball mill

    PubMed Central

    Eguaogie, Olga; Conlon, Patrick F; Ravalico, Francesco; Sweet, Jamie S T; Elder, Thomas B; Conway, Louis P; Lennon, Marc E; Hodgson, David R W

    2017-01-01

    Vibration ball-milling in a zirconia-lined vessel afforded clean and quantitative nucleophilic displacement reactions between 4-methoxybenzylthiolate salts and nucleoside 5′-halides or 5′-tosylates in five to 60 minutes. Under these conditions, commonly-encountered nucleoside cyclisation byproducts (especially of purine nucleosides) were not observed. Liquid-assisted grinding of the same 5'-iodide and 5′-tosylate substrates with potassium selenocyanate in the presence of DMF produced the corresponding 5′-selenocyanates in variable yields over the course of between one and eleven hours thereby avoiding the preparation and use of hygroscopic tetrabutylammonium salts. PMID:28179952

  15. 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

    2016-05-04

    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.

  16. A 31P-NMR study of the interaction of Mg2+ ions with nucleoside diphosphates.

    PubMed Central

    Tran-Dinh, S; Neumann, J M

    1977-01-01

    The interaction of Mg2+ with nucleoside disphosphates : ADP, GDP, CDP and UDP has been studied by phosphorus magnetic resonance spectroscopy in aqueous solution. The results show that these four nucleotides behave similarly, the Mg2+ ion binds to the alpha but not to the beta phosphate moiety. The strength of the interaction of Mg2+ ions with nucleoside diphosphates is weaker than with nucleoside triphosphates. The association of Mg2+ on the phosphate chain is stronger in a neutral than in an acid medium. PMID:14328

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

    PubMed

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

    1991-01-01

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

  18. The Sythesis of Certain Carbocyclic Nucleoside Analogs as Antiviral Agents.

    DTIC Science & Technology

    1985-12-01

    COMMAND Fort Detrick, Frederick, Maryland 21701-5012 Contract No. DAMD17-84-C-4135 DTIC Southern Research Institute t E L ECT E Birmingham, Alabama 35255...T.A~~~1ThL~~ ANrn~A NIIA GNS915/84-12/14/85"I S---- . PERFORMING ORG. REPORT NUMBER:..NUCLEOSIDE ANALOGS AS A TIVIR L A ENTS S E RIGOG E SoRI-KM- 85...CH, RR = NH2 0/NHH HOC HOCH HOCH X HO HO OH HO OH 4 6 a) R =CH3 a) X =0 b) R= l b) X =CH2 NH 2 ICH H H 7 %5 a specific inhibitor of S-adenosyl- L

  19. 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...

  20. Dynamic metabolic labeling of DNA in vivo with arabinosyl nucleosides.

    PubMed

    Neef, Anne B; Luedtke, Nathan W

    2011-12-20

    Commonly used metabolic labels for DNA, including 5-ethynyl-2'-deoxyuridine (EdU) and BrdU, are toxic antimetabolites that cause DNA instability, necrosis, and cell-cycle arrest. In addition to perturbing biological function, these properties can prevent metabolic labeling studies where subsequent tissue survival is needed. To bypass the metabolic pathways responsible for toxicity, while maintaining the ability to be metabolically incorporated into DNA, we synthesized and evaluated a small family of arabinofuranosyl-ethynyluracil derivatives. Among these, (2'S)-2'-deoxy-2'-fluoro-5-ethynyluridine (F-ara-EdU) exhibited selective DNA labeling, yet had a minimal impact on genome function in diverse tissue types. Metabolic incorporation of F-ara-EdU into DNA was readily detectable using copper(I)-catalyzed azide-alkyne "click" reactions with fluorescent azides. F-ara-EdU is less toxic than both BrdU and EdU, and it can be detected with greater sensitivity in experiments where long-term cell survival and/or deep-tissue imaging are desired. In contrast to previously reported 2'-arabino modified nucleosides and EdU, F-ara-EdU causes little or no cellular arrest or DNA synthesis inhibition. F-ara-EdU is therefore ideally suited for pulse-chase experiments aimed at "birth dating" DNA in vivo. As a demonstration, Zebrafish embryos were microinjected with F-ara-EdU at the one-cell stage and chased by BrdU at 10 h after fertilization. Following 3 d of development, complex patterns of quiescent/senescent cells containing only F-ara-EdU were observed in larvae along the dorsal side of the notochord and epithelia. Arabinosyl nucleoside derivatives therefore provide unique and effective means to introduce bioorthogonal functional groups into DNA for diverse applications in basic research, biotechnology, and drug discovery.

  1. Uridine Nucleoside Thiation: Gas-Phase Structures and Energetics

    NASA Astrophysics Data System (ADS)

    Hamlow, Lucas; Lee, Justin; Rodgers, M. T.; Berden, Giel; Oomens, Jos

    2016-06-01

    The naturally occurring thiated uridine nucleosides, 4-thiouridine (s4Urd) and 2-thiouridine (s2Urd), play important roles in the function and analysis of a variety of RNAs. 2-Thiouridine and its C5 modified analogues are commonly found in tRNAs and are believed to play an important role in codon recognition possibly due to their different structure, which has been shown by NMR to be predominantly C3'-endo. 2-Thiouridine may also play an important role in facilitating nonenzymatic RNA replication and transcription. 4-Thiouridine is a commonly used photoactivatable crosslinker that is often used to study RNA-RNA and RNA-protein cross-linking behavior. Differences in the base pairing between uracil and 4-thiouracil with adenine and guanine are an important factor in their role as a cross linker. The photoactivity of s4Urd may also aid in preventing near-UV lethality in cells. An understanding of their intrinsic structure in the gas-phase may help further elucidate the roles these modified nucleosides play in the regulation of RNAs. In this work, infrared multiple photon dissociation (IRMPD) action spectra of the protonated forms of s2Urd and s4Urd were collected in the IR fingerprint region. Structural information is determined by comparison with theoretical linear IR spectra generated from density functional theory calculations using molecular modeling to generate low-energy candidate structures. Present results are compared with analogous results for the protonated forms of uridine and 2'-deoxyuridine as well as solution phase NMR data and crystal structures.

  2. Uptake of intact nucleoside monophosphates by Bdellovibrio bacteriovorus 109J.

    PubMed Central

    Ruby, E G; McCabe, J B; Barke, J I

    1985-01-01

    The degraded nucleic acids and ribosomes of its prey cell provide Bdellovibrio bacteriovorus 109J with a source of ribonucleoside monophosphates and deoxyribonucleoside monophosphates for biosynthesis and respiration. We demonstrate that bdellovibrios, in contrast to almost all other bacteria, take up these nucleoside monophosphates into the cell in an intact, phosphorylated form. In this way they are able to assimilate more effectively the cellular contents of their prey. Studies with UMP and dTMP demonstrate that they are transported and accumulated against a concentration gradient, achieving internal levels at least 10 times the external levels. Treatment of the bdellovibrios with azide or carbonyl cyanide m-chlorophenylhydrazone eliminates their ability to either transport or maintain accumulated UMP and suggests the presence of a freely reversible exchange mechanism. There are at least two separate classes of transport systems for nucleoside monophosphates, each exhibiting partial specificity for either ribonucleoside monophosphates or deoxyribonucleoside monophosphates. Kinetic analyses of UMP transport in different developmental stages of strain 109J indicate that each stage expresses a single, saturable uptake system with a distinct apparent substrate affinity constant (Kt) of 104 microM in attack phase cells and 35 microM in prematurely released growth phase filaments. The capacity for transport of UMP by the growth phase filaments was 2.4 times that of the attack phase cells. These data, in addition to the apparent lack of environmental control of UMP transport capacity in attack phase cells, suggest that there are two transport systems for UMP in bdellovibrios and that the high-affinity, high-capacity growth phase system is developmentally regulated. PMID:4030692

  3. Discovery of the antibiotic phosacetamycin via a new mass spectrometry-based method for phosphonic acid detection.

    PubMed

    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

    2013-05-17

    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 have 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.

  4. 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

  5. Enzymatic synthesis and phosphorolysis of 4(2)-thioxo- and 6(5)-azapyrimidine nucleosides by E. coli nucleoside phosphorylases

    PubMed Central

    Stepchenko, Vladimir A; Miroshnikov, Anatoly I; Seela, Frank

    2016-01-01

    The trans-2-deoxyribosylation of 4-thiouracil (4SUra) and 2-thiouracil (2SUra), as well as 6-azauracil, 6-azathymine and 6-aza-2-thiothymine was studied using dG and E. coli purine nucleoside phosphorylase (PNP) for the in situ generation of 2-deoxy-α-D-ribofuranose-1-phosphate (dRib-1P) followed by its coupling with the bases catalyzed by either E. coli thymidine (TP) or uridine (UP) phosphorylases. 4SUra revealed satisfactory substrate activity for UP and, unexpectedly, complete inertness for TP; no formation of 2’-deoxy-2-thiouridine (2SUd) was observed under analogous reaction conditions in the presence of UP and TP. On the contrary, 2SU, 2SUd, 4STd and 2STd are good substrates for both UP and TP; moreover, 2SU, 4STd and 2’-deoxy-5-azacytidine (Decitabine) are substrates for PNP and the phosphorolysis of the latter is reversible. Condensation of 2SUra and 5-azacytosine with dRib-1P (Ba salt) catalyzed by the accordant UP and PNP in Tris∙HCl buffer gave 2SUd and 2’-deoxy-5-azacytidine in 27% and 15% yields, respectively. 6-Azauracil and 6-azathymine showed good substrate properties for both TP and UP, whereas only TP recognizes 2-thio-6-azathymine as a substrate. 5-Phenyl and 5-tert-butyl derivatives of 6-azauracil and its 2-thioxo derivative were tested as substrates for UP and TP, and only 5-phenyl- and 5-tert-butyl-6-azauracils displayed very low substrate activity. The role of structural peculiarities and electronic properties in the substrate recognition by E. coli nucleoside phosphorylases is discussed. PMID:28144328

  6. Enzymatic synthesis and phosphorolysis of 4(2)-thioxo- and 6(5)-azapyrimidine nucleosides by E. coli nucleoside phosphorylases.

    PubMed

    Stepchenko, Vladimir A; Miroshnikov, Anatoly I; Seela, Frank; Mikhailopulo, Igor A

    2016-01-01

    The trans-2-deoxyribosylation of 4-thiouracil ((4S)Ura) and 2-thiouracil ((2S)Ura), as well as 6-azauracil, 6-azathymine and 6-aza-2-thiothymine was studied using dG and E. coli purine nucleoside phosphorylase (PNP) for the in situ generation of 2-deoxy-α-D-ribofuranose-1-phosphate (dRib-1P) followed by its coupling with the bases catalyzed by either E. coli thymidine (TP) or uridine (UP) phosphorylases. (4S)Ura revealed satisfactory substrate activity for UP and, unexpectedly, complete inertness for TP; no formation of 2'-deoxy-2-thiouridine ((2S)Ud) was observed under analogous reaction conditions in the presence of UP and TP. On the contrary, (2S)U, (2S)Ud, (4S)Td and (2S)Td are good substrates for both UP and TP; moreover, (2S)U, (4S)Td and 2'-deoxy-5-azacytidine (Decitabine) are substrates for PNP and the phosphorolysis of the latter is reversible. Condensation of (2S)Ura and 5-azacytosine with dRib-1P (Ba salt) catalyzed by the accordant UP and PNP in Tris∙HCl buffer gave (2S)Ud and 2'-deoxy-5-azacytidine in 27% and 15% yields, respectively. 6-Azauracil and 6-azathymine showed good substrate properties for both TP and UP, whereas only TP recognizes 2-thio-6-azathymine as a substrate. 5-Phenyl and 5-tert-butyl derivatives of 6-azauracil and its 2-thioxo derivative were tested as substrates for UP and TP, and only 5-phenyl- and 5-tert-butyl-6-azauracils displayed very low substrate activity. The role of structural peculiarities and electronic properties in the substrate recognition by E. coli nucleoside phosphorylases is discussed.

  7. Chemoenzymatic Syntheses and Anti-HIV-1 Activity of Glucose-Nucleoside Conjugates as Prodrugs

    PubMed Central

    Rodríguez-Pérez, Tatiana; Fernández, Susana; Sanghvi, Yogesh S.; Detorio, Mervi; Schinazi, Raymond F.; Gotor, Vicente; Ferrero, Miguel

    2010-01-01

    Phosphodiester linked conjugates of various nucleosides such as d4U, d4T, IdUrd, ddI, ddA, virazole, ara-A and ara-C containing a glucosyl moiety have been described. These compounds were designed to act as prodrugs, where the corresponding 5′-monophosphates may be generated intracellularly. The synthesis of the glycoconjugates was achieved in good yields by condensation of a glucosyl phosphoramidite 7 with nucleosides in the presence of an activating agent. It was demonstrated that the glucose-conjugates improve water solubility of the nucleoside analogues, for example up to 31-fold for ara-A conjugate compared to ara-A alone. The new conjugates were tested for their anti-HIV-1 activity in human lymphocytes. These derivatives offer a convenient design for potential prodrug candidates with the possibility to improve the physicochemical properties and therapeutic activity of nucleoside analogues. PMID:21077659

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

    PubMed

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

    2015-09-01

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

  9. Complete genome sequence of Bacillus amyloliquefaciens XH7, which exhibits production of purine nucleosides.

    PubMed

    Yang, Huilin; Liao, Yuling; Wang, Bin; Lin, Ying; Pan, Li

    2011-10-01

    Here, we report the complete annotated genome sequence of Bacillus amyloliquefaciens XH7, which is used to produce purine nucleosides in industry. The genome sequence will allow for the characterization of the molecular mechanisms underlying its beneficial properties.

  10. 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.

  11. 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

  12. Poly(vinylidene fluoride) Containing Phosphonic Acid as Anticorrosion Coating for Steel.

    PubMed

    Banerjee, Sanjib; Wehbi, Mohammad; Manseri, Abdellatif; Mehdi, Ahmad; Alaaeddine, Ali; Hachem, Ali; Ameduri, Bruno

    2017-02-22

    Vinylidene fluoride (VDF)-based copolymers bearing pendant phosphonic acid function for potential application as anticorrosion coatings were synthesized via free radical copolymerization of VDF with a new phosphorus containing 2-trifluoromethacrylate monomer, (dimethoxyphosphoryl)methyl 2-(trifluoromethyl)acrylate (MAF-DMP). MAF-DMP was prepared from 2-trifluoromethacrylic acid in 60% overall yield. Radical copolymerizations of VDF with MAF-DMP initiated by tert-amyl peroxy-2-ethylhexanoate at varying ([VDF]0/[MAF-DMP]0) feed ratios led to several poly(VDF-co-MAF-DMP) copolymers having different molar percentages of VDF (79-96%) and number-average molecular weights (Mn's) up to ca. 10 000 g mol(-1) in fair yields (47-53%). Determination of the composition and microstructure of all the synthesized copolymers was done by (1)H and (19)F NMR spectroscopies. The monomer reactivity ratios of this new VDF/MAF-DMP pair were also determined (rVDF = 0.76 ± 0.34 and rMAF-DMP = 0 at 74 °C). The resulting poly(VDF-co-MAF-DMP) copolymers exhibited high melting temperature (162-171 °C, with respect to the VDF content), and the degree of crystallinity reached up to 51%. Finally, the pendant dimethyl phosphonate ester groups of the synthesized poly(VDF-co-MAF-DMP) copolymer were quantitatively hydrolyzed, giving rise to novel phosphonic acid-functionalized PVDF (PVDF-PA). In comparison to hydrophobic poly(VDF-co-MAF-DMP) copolymers (the water contact angle, WCA, was 98°), the hydrophilic character of the PVDF-PA was found to be surprisingly rather pronounced, exhibiting low WCA (15°). Finally, steel plates coated with PVDF-PA displayed satisfactory anticorrosion properties under simulated seawater environment.

  13. GRASr2 evaluation of aliphatic acyclic and alicyclic terpenoid tertiary alcohols and structurally related substances used as flavoring ingredients.

    PubMed

    Marnett, Lawrence J; Cohen, Samuel M; Fukushima, Shoji; Gooderham, Nigel J; Hecht, Stephen S; Rietjens, Ivonne M C M; Smith, Robert L; Adams, Timothy B; Bastaki, Maria; Harman, Christie L; McGowen, Margaret M; Taylor, Sean V

    2014-04-01

    This publication is the 1st in a series of publications by the Expert Panel of the Flavor and Extract Manufacturers Assoc. summarizing the Panel's 3rd re-evaluation of Generally Recognized as Safe (GRAS) status referred to as the GRASr2 program. In 2011, the Panel initiated a comprehensive program to re-evaluate the safety of more than 2700 flavor ingredients that have previously met the criteria for GRAS status under conditions of intended use as flavor ingredients. Elements that are fundamental to the safety evaluation of flavor ingredients include exposure, structural analogy, metabolism, pharmacokinetics, and toxicology. Flavor ingredients are evaluated individually and in the context of the available scientific information on the group of structurally related substances. Scientific data relevant to the safety evaluation of the use of aliphatic acyclic and alicyclic terpenoid tertiary alcohols and structurally related substances as flavoring ingredients are evaluated. The group of aliphatic acyclic and alicyclic terpenoid tertiary alcohols and structurally related substances was reaffirmed as GRAS (GRASr2) based, in part, on their rapid absorption, metabolic detoxication, and excretion in humans and other animals; their low level of flavor use; the wide margins of safety between the conservative estimates of intake and the no-observed-adverse effect levels determined from subchronic studies and the lack of significant genotoxic and mutagenic potential.

  14. 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.

  15. 1-Ammonio-1-phosphono-pentane-1-phospho-nic acid.

    PubMed

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

    2008-11-26

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

  16. 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

  17. 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.

  18. [Antiherpesviral activity of acycloguanosine H-phosphonate in experiments using laboratory animals].

    PubMed

    Andronova, V L; Galegov, G A; Ias'ko, M V; Kukhanova, M K; Kochetkov, S N; Skoblov, Iu S

    2011-01-01

    A study of the antiherpesviral activity of acycloguanosine (ACG) H-phosphonate (ACG-P) on a model of fatal herpesvirus infection in inbred BALB/c albino mice has established that ACG-P reduces death rates in the animals, considerably increases their average lifespan, and significantly decreases brain virus titers with both 60% mortality in the control and 92% mortality in the control group. There was also a significant inhibition of herpes simplex virus type 1 (HSV-1) replication in the brain tissue of animals receiving ACG-P on a model of ACG-resistant HSV-1/L2/RACG(TK-).

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

    NASA Astrophysics Data System (ADS)

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

    2016-08-01

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

  20. 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.

  1. Salvadenosine, a 5'-deoxy-5'-(methylthio) nucleoside from the Bahamian tunicate Didemnum sp.

    PubMed

    Jamison, Matthew T; Boddy, Christopher N; Molinski, Tadeusz F

    2014-11-07

    Salvadenosine, (1) a rare 5'-deoxy-5'-(methylthio) nucleoside, was isolated from the deep-water Bahaman tunicate Didemnum sp. The structure was solved by integrated analysis of MS and 1D and 2D NMR data. We revise the structure of the known natural product, hamiguanosinol, which is a constitutional isomer of 1, to 5 by interpretation of the spectroscopic data and comparison with synthesized nucleosides.

  2. Aqueous microwave-assisted cross-coupling reactions applied to unprotected nucleosides

    PubMed Central

    Hervé, Gwénaëlle; Len, Christophe

    2015-01-01

    Metal catalyzed cross-coupling reactions have been the preferred tools to access to modified nucleosides (on the C5-position of pyrimidines and on the C7- or C8-positions of purines). Our objective is to focus this mini-review on the Suzuki-Miyaura and on the Heck cross-couplings of nucleosides using microwave irradiations which is an alternative technology compatible with green chemistry and sustainable development PMID:25741506

  3. The Synthesis and Study of Azole Carboxamide Nucleosides as Agents Active Against RNA Viruses.

    DTIC Science & Technology

    1986-09-15

    5012 62770A 62770A8,1. AH 355 11. TITLE (Include Security Classification) The Synthesis and Study of Azole Carboxamide Nucleosides as Agents Active...broad-spectrum antiviral agent has stimulated a great deal of effort toward the chemical synthesis of nucleosides of other azole heterocycles. During the...4 II. Chemistry and Discussion . . .. .. . 6 1. Synthesis of Certain 5’-Substituted Derivatives of Ribavirin and Tiazofurin . . .. . 6 2

  4. 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.

  5. Classification of lung cancer patients and controls by chromatography of modified nucleosides in serum

    USGS Publications Warehouse

    McEntire, John E.; Kuo, Kenneth C.; Smith, Mark E.; Stalling, David L.; Richens, Jack W.; Zumwalt, Robert W.; Gehrke, Charles W.; Papermaster, Ben W.

    1989-01-01

    A wide spectrum of modified nucleosides has been quantified by high-performance liquid chromatography in serum of 49 male lung cancer patients, 35 patients with other cancers, and 48 patients hospitalized for nonneoplastic diseases. Data for 29 modified nucleoside peaks were normalized to an internal standard and analyzed by discriminant analysis and stepwise discriminant analysis. A model based on peaks selected by a stepwise discriminant procedure correctly classified 79% of the cancer and 75% of the noncancer subjects. It also demonstrated 84% sensitivity and 79% specificity when comparing lung cancer to noncancer subjects, and 80% sensitivity and 55% specificity in comparing lung cancer to other cancers. The nucleoside peaks having the greatest influence on the models varied dependent on the subgroups compared, confirming the importance of quantifying a wide array of nucleosides. These data support and expand previous studies which reported the utility of measuring modified nucleoside levels in serum and show that precise measurement of an array of 29 modified nucleosides in serum by high-performance liquid chromatography with UV scanning with subsequent data modeling may provide a clinically useful approach to patient classification in diagnosis and subsequent therapeutic monitoring.

  6. Nature's combinatorial biosynthesis and recently engineered production of nucleoside antibiotics in Streptomyces.

    PubMed

    Chen, Shawn; Kinney, William A; Van Lanen, Steven

    2017-04-01

    Modified nucleosides produced by Streptomyces and related actinomycetes are widely used in agriculture and medicine as antibacterial, antifungal, anticancer and antiviral agents. These specialized small-molecule metabolites are biosynthesized by complex enzymatic machineries encoded within gene clusters in the genome. The past decade has witnessed a burst of reports defining the key metabolic processes involved in the biosynthesis of several distinct families of nucleoside antibiotics. Furthermore, genome sequencing of various Streptomyces species has dramatically increased over recent years. Potential biosynthetic gene clusters for novel nucleoside antibiotics are now apparent by analysis of these genomes. Here we revisit strategies for production improvement of nucleoside antibiotics that have defined mechanisms of action, and are in clinical or agricultural use. We summarize the progress for genetically manipulating biosynthetic pathways for structural diversification of nucleoside antibiotics. Microorganism-based biosynthetic examples are provided and organized under genetic principles and metabolic engineering guidelines. We show perspectives on the future of combinatorial biosynthesis, and present a working model for discovery of novel nucleoside natural products in Streptomyces.

  7. The human concentrative and equilibrative nucleoside transporter families, SLC28 and SLC29.

    PubMed

    Young, James D; Yao, Sylvia Y M; Baldwin, Jocelyn M; Cass, Carol E; Baldwin, Stephen A

    2013-01-01

    Nucleoside transport in humans is mediated by members of two unrelated protein families, the SLC28 family of cation-linked concentrative nucleoside transporters (CNTs) and the SLC29 family of energy-independent, equilibrative nucleoside transporters (ENTs). These families contain three and four members, respectively, which differ both in the stoichiometry of cation coupling and in permeant selectivity. Together, they play key roles in nucleoside and nucleobase uptake for salvage pathways of nucleotide synthesis. Moreover, they facilitate cellular uptake of several nucleoside and nucleobase drugs used in cancer chemotherapy and treatment of viral infections. Thus, the transporter content of target cells can represent a key determinant of the response to treatment. In addition, by regulating the concentration of adenosine available to cell surface receptors, nucleoside transporters modulate many physiological processes ranging from neurotransmission to cardiovascular activity. This review describes the molecular and functional properties of the two transporter families, with a particular focus on their physiological roles in humans and relevance to disease treatment.

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

    PubMed

    Baldessari, Alicia; Iglesias, Luis E

    2012-01-01

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

  9. 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.

  10. 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.

  11. Screening of nerve agent markers with hollow fiber-chemosorption of phosphonic acids.

    PubMed

    Holmgren, Karin Höjer; Gustafsson, Tomas; Östin, Anders

    2016-10-15

    This report describes a method developed for extracting nerve gas markers such as phosphonic acids from urine and other aqueous samples. It involves single-step microextraction with chemosorption to hollow fibers that have been pre-soaked in a solution containing a derivatization reagent (3,5 triflouro methyl benzene diazomethane). The derivatives it forms with phosphonic acids can be sensitively detected by mass spectrometric detectors operating in negative chemical ionization (NCI) mode. Limits of quantification obtained in analyses of water and urine extracts by GC/MS in negative chemical ionization and selected ion monitoring mode were 0.1-10 and 0.5-10ng/mL, respectively. Pentaflourophenyl diazomethane can also be used as a derivatization reagent, and the micro-extracts (which generate low background signals) can be sensitively analyzed by GC-MS/MS in NCI selected reaction monitoring (SRM) mode, using two specific transitions for both reagents. Thus, this sensitive approach can be flexibly modified to obtain confirmatory information, or address potential problems caused by interferences in some samples.

  12. 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

  13. 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

  14. 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.

  15. Linked Nickel Metallacrowns from a Phosphonate/2-Pyridyloximate Blend of Ligands: Structure and Magnetic Properties.

    PubMed

    Escuer, Albert; Mayans, Júlia; Font-Bardia, Mercè

    2016-03-21

    In the present work, four new Ni(II) clusters with nuclearities ranging between Ni4 and Na2Ni8 were synthesized, employing the versatile ligand phenylphosphonate and 6-methylpyridylaldoximate as the coligand. Crystallographic data show that the tetranuclear complex [Ni4(6-MepaoH)4(PhPO3)2(OH)2(MeOH)4](OH)2 (1) consists of two dimers linked by phosphonate bridges, whereas [Cs2Ni6(6-Mepao)6(PhPO3)3(OH)2(H2O)8] (2), Cs[Ni8(6-MepaoH)6(6-Mepao)6(PhPO3)3](ClO4)5 (3), and [Ni8Na2(BzO)6(6-Mepao)6(PhPO3)3] (4) are built from phosphonato-linked {Ni3(6-Mepao)3} metallacycles. The [9-MC(Ni(II)(6-Mepao))-3] fragments in 2-4 show the unusual coordination of additional Cs(+), Na(+), and/or Ni(II) cations. Direct-current magnetic measurements were carried in the 300-2 K range. Analysis of the experimental data revealed a complex response with strong antiferromagnetic interactions mediated by the oximato bridges and weak interactions mediated by the phosphonate ones.

  16. Preparation and characterization of N-methylene phosphonic and quaternized chitosan composite membranes for electrolyte separations.

    PubMed

    Saxena, Arunima; Kumar, Arvind; Shahi, Vinod K

    2006-11-15

    Chitosan was functionalized either by introducing a phosphonic acid group or by quaternization of existing primary ammonium groups in order to make it a water-soluble material. Functionalized chitosans and poly(vinyl alcohol) (PVA)-based nanoporous charged membranes were prepared in aqueous media and gelated in methanol at 10 degrees C to tailor their pore structure. These membranes were extensively characterized for their physicochemical, electrochemical, and permeation characteristics using FTIR, TGA, DSC, water content, ion-exchange capacity, ionic transport properties, and membrane permeability studies. N-Methylene phosphonic chitosan (NMPC)/PVA-based membranes exhibited mild cation selectivity and quaternized chitosan (QC)/PVA composite membranes had mild anion selectivity, while a blend of NMPC-QC/PVA membranes exhibited weak cation selectivity because of formation of zwitterionic structure. Viscosity measurements and interaction studies for individual and mixed solutions of NMPC and QC were carried out for the prediction of charge interactions between -PO3H2 and -N+(CH3)3 groups and effect on molecular weight due to functionalization. Elaborate electrochemical and permeation experiments were conducted in order to predict suitability of these membranes for the separation of mono- and bivalent electrolytes based on their hydrated ionic radius, and it was found that among all the synthesized membranes, PC/QC-30 had the highest relative permeability, which may extend its suitability for electrolyte separations. Observations were correlated with equivalent pore radius of the different membranes as estimated by membrane permeability measurements.

  17. New cleft-like molecules and macrocycles from phosphonate substituted spirobisindanol.

    PubMed

    Consiglio, Giuseppe A; Failla, Salvatore; Finocchiaro, Paolo

    2008-03-20

    We have synthetized medium-sized cyclophanes and macrocycles containing phosphonic groups, directly linked to the aromatic rings of the phanes or as pendant arms,for use as specific receptors for the selective complexation of neutral guests or for complexing lanthanides, as luminescent sensors and for diagnostic bioassays in medicine.Furthermore, because it would be of great interest for biochemistry as well as for pharmacological studies to dispose of preorganized rigid chiral hosts for biorelevant molecules we designed inter alia, some new chiral macrocycles capable of a triple binding mode and we used them for constructing macrocycles that could also be of interest for chiral recognition and chiral separations. Thus, in this paper we shall review the salient aspects of some macrocycles synthetized in our laboratory, all possessing the phosphonate moiety and a spirobisindanol scaffold and able to act as complexing agents for cations and organic substrates. In particular, we shall describe their NMR characterization, their stereochemistry in solution and in the solid state, and their use as chiral receptors for biorelevant molecules. Chiral HPLC resolution of some of them is also reported.

  18. 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.

  19. Differential effects of phosphonic analogues of GABA on GABA(B) autoreceptors in rat neocortical slices.

    PubMed

    Ong, J; Marino, V; Parker, D A; Kerr, D I

    1998-04-01

    The effects of five phosphonic derivatives of GABA on the release of [3H]-GABA from rat neocortical slices, preloaded with [3H]-GABA, were investigated. Phaclofen and 4-aminobutylphosphonic acid (4-ABPA) increased the overflow of [3H] evoked by electrical stimulation (2 Hz) in a concentration-dependent manner, with similar potencies (phaclofen EC50=0.3 mmol/l, 4-ABPA EC50=0.4 mmol/l). At 3 mmol/l, phaclofen increased the release of [3H]-GABA by 82.6+/-8.6%, and 4-ABPA increased the release by 81.3+/-9.0%. 2-Amino-ethylphosphonic acid (2-AEPA) increased the overflow of [3H] by 46.8+/-10.9% at the highest concentration tested (3 mmol/l). In contrast, the lower phosphonic homologue 3-aminopropylphosphonic acid (3-APPA), and 2-amino-2-(p-chlorophenyl)-ethylphosphonic acid (2-CPEPA), a baclofen analogue, did not modify the stimulated overflow. These results suggest that phaclofen, 4-ABPA and 2-AEPA are antagonists at GABA(B) autoreceptors, the latter being the weakest antagonist, whilst neither 3-APPA nor 2-CPEPA are active at these receptors. Since phaclofen, 4-ABPA and 2-CPEPA are antagonists and 3-APPA a partial agonist/antagonist on GABA(B) heteroreceptors, the lack of effect of 3-APPA and 2-CPEPA on [3H]-GABA release in this study suggests that GABA(B) autoreceptors may be pharmacologically distinct from the heteroreceptors.

  20. Covalent modification of calcium hydroxyapatite surface by grafting phenyl phosphonate moieties

    SciTech Connect

    Aissa, Abdallah; Debbabi, Mongi; Gruselle, Michel Thouvenot, Rene; Gredin, Patrick; Traksmaa, Rainer; Tonsuaadu, Kaia

    2007-08-15

    The reaction between phenyl phosphonic dichloride (C{sub 6}H{sub 5}P(O)Cl{sub 2}) and synthetic calcium hydroxy- and fluorapatite has been investigated. The presence of mono- or polymeric (C{sub 6}H{sub 5}PO) fragment bound to hydroxyapatite was evidenced by IR, and solid-state {sup 31}P NMR spectroscopy. X-ray powder analysis has shown that the apatitic structure remains unchanged during the reaction. In contrast, no reaction was found using fluorapatite. According to the results found for these two different apatites a mechanism was proposed for the formation of covalent P-O-P bonds as the result of a reaction between the C{sub 6}H{sub 5}P(O)Cl{sub 2} organic reagent and (HPO{sub 4}){sup -} and/or OH{sup -} ions of the hydroxyapatite. - Graphical abstract: Representation of the first step of the reaction between the phenyl phosphonic dichloride and the hydroxyl groups on the surface of the apatite, leading to covalent P-O-P bond with elimination of HCl.

  1. Design, synthesis and pharmacological screening of β-amino-, thiadiazole/thiadiazine-phosphonate based triazole motifs as antimicrobial/cytotoxic agents.

    PubMed

    Abdou, Wafaa M; Ganoub, Neven A; Sabry, Eman

    2014-09-01

    Three different series of phosphonate derivatives, β-amino- and fused thiadiazolo/thiadiazine-phosphonates have been synthesized using the addition and/or addition-cyclization protocol of Horner-Wadsworth-Emmons (HWE) reagents to 1,2,4-triazole-3-thiols. The design of potentially antimicrobial and anticancer phosphor esters relied on the results of computer-assisted molecular modeling. All synthesized phosphonates were evaluated for their in vitro antimicrobial activities while anticancer properties were determined for eight out of twenty new phosphonates. The tested phosphonates, except for compounds that have a nitrile moiety, exhibited moderate to significant antimicrobial activity. Nevertheless, the most active compounds were fused thiadiazole-phosphonates, which inhibited the growth of both Gram-negative and Gram-positive bacteria better than β-aminophosphonates and fused thiadiazolophosphonates. In parallel, the antitumor activity screenings of selected phosphonates from each series and substrate 1 were also done. Their antitumor properties against ten carcinoma cell lines, including breast (MCF7, MDA-MB- 231/ ATCC, MDA-MB-435, BT-549), ovarian (IGROVI, OVCAR-3, SK-OV-3), prostate (PX-3, PU-145), and liver (HEPG2), were investigated. The results showed that all synthesized compounds reflected remarkable antitumor activity against breast (especially MDA-MB-231/ATCC and BT-549), and prostate carcinoma cell lines (PC-3 and DU-145), whereas a moderate to good effect on ovarian and liver cancer cells was observed.

  2. Activation of anti-reverse transcriptase nucleotide analogs by nucleoside diphosphate kinase: improvement by alpha-boranophosphate substitution.

    PubMed

    Schneider, B; Meyer, P; Sarfati, S; Mulard, L; Guerreiro, C; Boretto, J; Janin, J; Véron, M; Deville-Bonne, D; Canard, B

    2001-01-01

    Nucleoside activation by nucleoside diphosphate kinase and inhibition of HIV-1 reverse transcriptase were studied comparatively for a new class of nucleoside analogs with a borano (BH3-) or a thio (SH) group on the alpha-phosphate. Both the alpha-Rp-borano derivatives of AZT and d4T improved phosphorylation by NDP kinase, inhibition of reverse transcription as well as stability of alpha-borano nonophosphate derivatives in terminated viral DNA chain.

  3. 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

  4. 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.

  5. Inhibition and Structure of Toxoplasma gondii Purine Nucleoside Phosphorylase

    PubMed Central

    Donaldson, Teraya M.; Cassera, María B.; Ho, Meng-Chiao; Zhan, Chenyang; Merino, Emilio F.; Evans, Gary B.; Tyler, Peter C.; Almo, Steven C.; Schramm, Vern L.

    2014-01-01

    The intracellular pathogen Toxoplasma gondii is a purine auxotroph that relies on purine salvage for proliferation. We have optimized T. gondii purine nucleoside phosphorylase (TgPNP) stability and crystallized TgPNP with phosphate and immucillin-H, a transition-state analogue that has high affinity for the enzyme. Immucillin-H bound to TgPNP with a dissociation constant of 370 pM, the highest affinity of 11 immucillins selected to probe the catalytic site. The specificity for transition-state analogues indicated an early dissociative transition state for TgPNP. Compared to Plasmodium falciparum PNP, large substituents surrounding the 5′-hydroxyl group of inhibitors demonstrate reduced capacity for TgPNP inhibition. Catalytic discrimination against large 5′ groups is consistent with the inability of TgPNP to catalyze the phosphorolysis of 5′-methylthioinosine to hypoxanthine. In contrast to mammalian PNP, the 2′-hydroxyl group is crucial for inhibitor binding in the catalytic site of TgPNP. This first crystal structure of TgPNP describes the basis for discrimination against 5′-methylthioinosine and similarly 5′-hydroxy-substituted immucillins; structural differences reflect the unique adaptations of purine salvage pathways of Apicomplexa. PMID:24585883

  6. 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.

  7. 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.

  8. Phosphonate-functionalized large pore 3-D cubic mesoporous (KIT-6) hybrid as highly efficient actinide extracting agent.

    PubMed

    Lebed, Pablo J; de Souza, Kellen; Bilodeau, François; Larivière, Dominic; Kleitz, Freddy

    2011-11-07

    A new type of radionuclide extraction material is reported based on phosphonate functionalities covalently anchored on the mesopore surface of 3-D cubic mesoporous silica (KIT-6). The easily prepared nanoporous hybrid shows largely superior performance in selective sorption of uranium and thorium as compared to the U/TEVA commercial resin and 2-D hexagonal SBA-15 equivalent.

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

    PubMed

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

    2011-01-01

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

  10. Substrate specificity of pyrimidine nucleoside phosphorylases of NP-II family probed by X-ray crystallography and molecular modeling

    NASA Astrophysics Data System (ADS)

    Balaev, V. V.; Lashkov, A. A.; Prokofev, I. I.; Gabdulkhakov, A. G.; Seregina, T. A.; Mironov, A. S.; Betzel, C.; Mikhailov, A. M.

    2016-09-01

    Pyrimidine nucleoside phosphorylases, which are widely used in the biotechnological production of nucleosides, have different substrate specificity for pyrimidine nucleosides. An interesting feature of these enzymes is that the three-dimensional structure of thymidine-specific nucleoside phosphorylase is similar to the structure of nonspecific pyrimidine nucleoside phosphorylase. The three-dimensional structures of thymidine phosphorylase from Salmonella typhimurium and nonspecific pyrimidine nucleoside phosphorylase from Bacillus subtilis in complexes with a sulfate anion were determined for the first time by X-ray crystallography. An analysis of the structural differences between these enzymes demonstrated that Lys108, which is involved in the phosphate binding in pyrimidine nucleoside phosphorylase, corresponds to Met111 in thymidine phosphorylases. This difference results in a decrease in the charge on one of the hydroxyl oxygens of the phosphate anion in thymidine phosphorylase and facilitates the catalysis through SN2 nucleophilic substitution. Based on the results of X-ray crystallography, the virtual screening was performed for identifying a potent inhibitor (anticancer agent) of nonspecific pyrimidine nucleoside phosphorylase, which does not bind to thymidine phosphorylase. The molecular dynamics simulation revealed the stable binding of the discovered compound—2-pyrimidin-2-yl-1H-imidazole-4-carboxylic acid—to the active site of pyrimidine nucleoside phosphorylase.

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

    PubMed

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

    2013-01-01

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

  12. The role of minerals in the thermal alteration of organic matter--IV. Generation of n-alkanes, acyclic isoprenoids, and alkenes in laboratory experiments.

    PubMed

    Huizinga, B J; Tannenbaum, E; Kaplan, I R

    1987-01-01

    A series of pyrolysis experiments, utilizing two different immature oil-prone kerogens ("type I": Green River Formation kerogen; "Type II": Monterey Formation kerogen) mixed with common sedimentary minerals (calcite, illite, or Na-montmorillonite), was conducted to study the effects of minerals on the generation of n-alkanes, acyclic isoprenoids, and alkenes during laboratory-simulated catagenesis of kerogen. The influence of clay minerals on the aliphatic hydrocarbons is critically dependent on the water concentration during laboratory thermal maturation. Under extremely low contents of water (i.e., dry pyrolysis, where only pyrolysate water is present), C12(+) -range n-alkanes and acyclic isoprenoids are mostly destroyed by montmorillonite but undergo only minor alteration with illite. Both clay minerals significantly reduce alkene formation during dry pyrolysis. Under hydrous conditions (mineral/water = 2:1), the effects of the clay minerals are substantially reduced. In addition, the dry pyrolysis experiments show that illite and montmorillonite preferentially retain large amounts of the polar constituents of bitumen, but not n-alkanes or acyclic isoprenoids. Therefore, bitumen fractionation according to polarity differences occurs in the presence of these clay minerals. By this process, n-alkanes and acyclic isoprenoids are concentrated in the bitumen fraction that is not strongly adsorbed on the clay matrices. The extent of these concentrations effects is greatly diminished during hydrous pyrolysis. In contrast, calcite has no significant influence on the thermal evolution of the hydrocarbons. In addition, calcite is incapable of retaining bitumen. Therefore, the fractionation of n-alkanes or acyclic isoprenoids relative to the polar constituents of bitumen is insignificant in the presence of calcite.

  13. Enantioselective Lewis acid-catalyzed Mukaiyama-Michael reactions of acyclic enones. Catalysis by allo-threonine-derived oxazaborolidinones.

    PubMed

    Wang, Xiaowei; Adachi, Shinya; Iwai, Hiroyoshi; Takatsuki, Hiroshi; Fujita, Katsuhiro; Kubo, Mikako; Oku, Akira; Harada, Toshiro

    2003-12-26

    allo-Threonine-derived O-aroyl-B-phenyl-N-tosyl-1,3,2-oxazaborolidin-5-ones 1g,n catalyze the asymmetric Mukaiyama-Michael reaction of acyclic enones with a trimethylsilyl ketene S,O-acetal in high enantioselectivity. A range of alkenyl methyl ketones is successfully employed as Michael acceptors affording ee values of 85-90% by using 10 mol % of the catalyst. The use of 2,6-diisopropylphenol and tert-butyl methyl ether as additives is found to be essential to achieve high enantioselectivity in these reactions. The effects of the additives are discussed in terms of the retardation of an Si(+)-catalyzed racemic pathway, which seriously deteriorates the enantioselectivity of asymmetric Mukaiyama-Michael reactions. A working model for asymmetric induction is proposed based on correlation between catalyst structures and enantioselectivities.

  14. Identification and geochemical significance of cyclic di-and trisulphides with linear and acyclic isoprenoid carbon skeletons in immature sediments

    NASA Astrophysics Data System (ADS)

    Kohnen, Math E. L.; Sinninghe Damsté, Jaap S.; ten Haven, H. L.; Van Dalen, A. C. Kock; Schouten, Stefan; De Leeuw, Jan W.

    1991-12-01

    Homologous series (C 15-C 24) of novel 3- n-alkyl-1,2-dithianes and 3- n-alkyl-6-methyl-1,2-di-thianes have been identified in immature sediments. The identification of these compounds was based on comparison of mass spectra and Chromatographie data with those of synthesized 3-methyl-6-tridecyll, 2-dithiane. In addition, 4-methyl-3-(3,7,11-trimethyldodecyl)-1,2-dithiane, 4-(4,8,12-trimethyltridecyl)-1,2-dithiane, 5-methyl-4-(3,7,11-trimethyldodecyl)-1,2,3-trithiepane, and a 1,2-dithiane possessing a pentakishomohopane carbon skeleton were tentatively assigned on the basis of mass spectral characteristics, selective chemolysis, and desulphurisation. The occurrence of these cyclic di-and trisulphides with linear, acyclic isoprenoid and hopanoid carbon skeletons in thermally immature sediments indicates that inorganic polysulphides are incorporated into functionalised lipids during the early stages of diagenesis.

  15. 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

    2015-11-07

    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.

  16. Wavelet Entropy and Directed Acyclic Graph Support Vector Machine for Detection of Patients with Unilateral Hearing Loss in MRI Scanning

    PubMed Central

    Wang, Shuihua; Yang, Ming; Du, Sidan; Yang, Jiquan; Liu, Bin; Gorriz, Juan M.; Ramírez, Javier; Yuan, Ti-Fei; Zhang, Yudong

    2016-01-01

    Highlights We develop computer-aided diagnosis system for unilateral hearing loss detection in structural magnetic resonance imaging.Wavelet entropy is introduced to extract image global features from brain images. Directed acyclic graph is employed to endow support vector machine an ability to handle multi-class problems.The developed computer-aided diagnosis system achieves an overall accuracy of 95.1% for this three-class problem of differentiating left-sided and right-sided hearing loss from healthy controls. Aim: Sensorineural hearing loss (SNHL) is correlated to many neurodegenerative disease. Now more and more computer vision based methods are using to detect it in an automatic way. Materials: We have in total 49 subjects, scanned by 3.0T MRI (Siemens Medical Solutions, Erlangen, Germany). The subjects contain 14 patients with right-sided hearing loss (RHL), 15 patients with left-sided hearing loss (LHL), and 20 healthy controls (HC). Method: We treat this as a three-class classification problem: RHL, LHL, and HC. Wavelet entropy (WE) was selected from the magnetic resonance images of each subjects, and then submitted to a directed acyclic graph support vector machine (DAG-SVM). Results: The 10 repetition results of 10-fold cross validation shows 3-level decomposition will yield an overall accuracy of 95.10% for this three-class classification problem, higher than feedforward neural network, decision tree, and naive Bayesian classifier. Conclusions: This computer-aided diagnosis system is promising. We hope this study can attract more computer vision method for detecting hearing loss. PMID:27807415

  17. Wavelet Entropy and Directed Acyclic Graph Support Vector Machine for Detection of Patients with Unilateral Hearing Loss in MRI Scanning.

    PubMed

    Wang, Shuihua; Yang, Ming; Du, Sidan; Yang, Jiquan; Liu, Bin; Gorriz, Juan M; Ramírez, Javier; Yuan, Ti-Fei; Zhang, Yudong

    2016-01-01

    Highlights We develop computer-aided diagnosis system for unilateral hearing loss detection in structural magnetic resonance imaging.Wavelet entropy is introduced to extract image global features from brain images. Directed acyclic graph is employed to endow support vector machine an ability to handle multi-class problems.The developed computer-aided diagnosis system achieves an overall accuracy of 95.1% for this three-class problem of differentiating left-sided and right-sided hearing loss from healthy controls. Aim: Sensorineural hearing loss (SNHL) is correlated to many neurodegenerative disease. Now more and more computer vision based methods are using to detect it in an automatic way. Materials: We have in total 49 subjects, scanned by 3.0T MRI (Siemens Medical Solutions, Erlangen, Germany). The subjects contain 14 patients with right-sided hearing loss (RHL), 15 patients with left-sided hearing loss (LHL), and 20 healthy controls (HC). Method: We treat this as a three-class classification problem: RHL, LHL, and HC. Wavelet entropy (WE) was selected from the magnetic resonance images of each subjects, and then submitted to a directed acyclic graph support vector machine (DAG-SVM). Results: The 10 repetition results of 10-fold cross validation shows 3-level decomposition will yield an overall accuracy of 95.10% for this three-class classification problem, higher than feedforward neural network, decision tree, and naive Bayesian classifier. Conclusions: This computer-aided diagnosis system is promising. We hope this study can attract more computer vision method for detecting hearing loss.

  18. OCTN1 is a high-affinity carrier of nucleoside analogs.

    PubMed

    Drenberg, Christina; Gibson, Alice A; Pounds, Stanley; Shi, Lei; Rhinehart, Dena; Li, Lie; Hu, Shuiying; Du, Guoqing; Nies, Anne T; Schwab, Matthias; Pabla, Navjotsingh; Blum, William; Gruber, Tanja A; Baker, Sharyn D; Sparreboom, Alex

    2017-02-16

    Resistance to xenobiotic nucleosides used to treat acute myeloid leukemia (AML) and other cancers remains a major obstacle to clinical management. One process suggested to participate in resistance is reduced uptake into tumor cells via nucleoside transporters, although precise mechanisms are not understood. Through transcriptomic profiling, we determined that low expression of the ergothioneine transporter OCTN1 (SLC22A4; ETT) strongly predicts poor event-free survival and overall survival in multiple cohorts of AML patients receiving treatment with the cytidine nucleoside analog cytarabine. Cell biological studies confirmed OCTN1-mediated transport of cytarabine and various structurally-related cytidine analogs, such as 2'deoxycytidine and gemcitabine, occurs through a saturable process that is highly sensitive to inhibition by the classic nucleoside transporter inhibitors dipyridamole and nitrobenzylmercaptopurine ribonucleoside (NBMPR). Our findings have immediate clinical implications given the potential of the identified transport system to help refine strategies that could improve patient survival across multiple cancer types where nucleoside analogs are used in cancer treatment.

  19. Evaluating the reproducibility of quantifying modified nucleosides from ribonucleic acids by LC–UV–MS

    PubMed Central

    Russell, Susan P.; Limbach, Patrick A.

    2013-01-01

    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

  20. 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.

  1. 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

  2. Simultaneous determination of 10 nucleosides and nucleobases in Antrodia camphorata using QTRAP LC-MS/MS.

    PubMed

    Chen, Fei; Zhang, Fengsu; Yang, Nianyun; Liu, Xunhong

    2014-09-01

    A liquid chromatography-triple-quadrupole linear ion trap mass spectrometry (LC-QTrap-MS) analysis has been developed for the identification and quantification of 10 nucleosides and nucleobases in extracts of Antrodia camphorata. The method was successfully used to qualitatively identify for six nucleosides namely, cytidine, uridine, inosine, guanosine, thymidine, adenosine and four nucleobases namely, uracil, guanine, xanthine, adenine in A. camphorata. Under optimized chromatographic conditions, good separation for 10 target compounds were obtained on an Agilent HC-C18(2) column (4.6 × 250 mm, 5 μm) eluted by a mobile phase of 5 mM ammonium acetate solution-methanol at a flow rate of 0.5 mL/min. Data acquisition was carried out in multiple reaction monitoring transition mode. Additional identification and confirmation of target compounds were performed using the enhanced product ion modus of the linear ion trap. It was the first report about simultaneous analysis of nucleosides and nucleobases in A. camphorata using this method. These results demonstrated that the QTRAP LC-MS/MS was a useful tool for quality evaluation of some medicinal plant products by using nucleosides and nucleobases as chemical markers. This method might also be utilized for the investigation of edible plant materials and agricultural products containing nucleosides and nucleobases.

  3. 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

  4. Supramolecular polymerization of a prebiotic nucleoside provides insights into the creation of sequence-controlled polymers

    SciTech Connect

    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; Fuentes-Cabrera, Miguel A

    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 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. 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.

  5. Supramolecular polymerization of a prebiotic nucleoside provides insights into the creation of sequence-controlled polymers

    DOE PAGES

    Wang, Jun; Bonnesen, Peter V; Rangel, E.; ...

    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

  6. Asymmetric Friedel-Crafts alkylations of indoles with dialkyl 3-oxoprop-1-enylphosphonates: organocatalytic enantioselective synthesis of alpha-indolyl phosphonates.

    PubMed

    Guo, Ying-Cen; Li, Dong-Ping; Li, Yu-Ling; Wang, Hong-Mei; Xiao, Wen-Jing

    2009-08-01

    Organocatalytic enantioselective synthesis of alpha-indolyl phosphonates has been successfully carried out via asymmetric Friedel-Crafts alkylation of substituted indoles with (E)-dialkyl 3-oxoprop-1-enylphosphonates in 48-82% yield and 73-96% ee.

  7. Phosphonic Acid Functionalized Asymmetric Phthalocyanines: Synthesis, Modification of Indium Tin Oxide (ITO), and Charge Transfer

    SciTech Connect

    Polaske, Nathan W.; Lin, Hsiao-Chu; Tang, Anna; Mayukh, Mayank; Oquendo, Luis E.; Green, John; Ratcliff, Erin L.; Armstrong, Neal R.; Saavedra, S. Scott; McGrath, Dominic V.

    2011-12-20

    Metalated and free-base A₃B-type asymmetric phthalocyanines (Pcs) bearing, in the asymmetric quadrant, a flexible alkyl linker of varying chain lengths terminating in a phosphonic acid (PA) group have been synthesized. Two parallel series of asymmetric Pc derivatives bearing aryloxy and arylthio substituents are reported, and their synthesis and characterization through NMR, combustion analysis, and MALDI-MS are described. We also demonstrate the modification of indium tin oxide (ITO) substrates using the PA functionalized asymmetric Pc derivatives and monitoring their electrochemistry. The PA functionalized asymmetric Pcs were anchored to the ITO surface through chemisorption and their electrochemical properties characterized using cyclic voltammetry to investigate the effects of PA structure on the thermodynamics and kinetics of charge transfer. Ionization energies of the modified ITO surfaces were measured using ultraviolet photoemission spectroscopy.

  8. A report on emergent uranyl binding phenomena by an amidoxime phosphonic acid co-polymer

    SciTech Connect

    Abney, C. W.; Das, S.; Mayes, R. T.; Kuo, L. -J.; Wood, J.; Gill, G.; Piechowicz, M.; Lin, Z.; Lin, W.; Dai, S.

    2016-01-01

    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 μ2-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.

  9. 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.

  10. Specific detection and properties of enzyme hydrolyzing phosphonate ester in serum.

    PubMed

    Han, G Y; Fan, X H; Jin, X B; Wang, D P

    1992-03-01

    An enzyme capable of hydrolyzing 4-methylumbelliferyl phenylphosphonate to 4-methylumbelliferone and phenylphosphonic acid has been detected in human serum. It has a Km value of 1.72 x 10(-4) mol/L, has an optimum pH of 8.8-9.1 in Tris buffer, and shows maximum activity at 60 degrees C (30 min). The enzymic activity can be inhibited by Na3PO4, EDTA, and cysteine. We saw no effect of CuSO4, adenosine, thymidine, NaN3, diethyl p-nitrophenyl phosphate, p-chloromercuribenzoate, isopropyl fluorophosphate, or eserine on the enzymic activity. The enzyme cannot hydrolyze substrates of phosphodiesterase I or alkaline phosphatase. The enzyme is considered a phosphonate esterase.

  11. 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

  12. New synthesis of silver phosphonate complexes from polymeric silver phenylethynide as a structure-directing precursor.

    PubMed

    Xie, Yun-Peng; Mak, Thomas C W

    2013-09-28

    Three new silver(I) phosphonate complexes have been synthesized from silver phenylethynide as a structure-directing precursor. Ag2(PhPO3)(H2O) displays a layer-type coordination network, Ag(3,5-dimethylpyrazole)2(PhPO3H) contains a dimeric unit, and {Ag8(dppm)4((t)BuPO3)2(ClO4)(NO3)(0.67)(H2O)(1.33)}·(ClO4)(2.33)·(CH3OH)(6.67) features an octanuclear composite cluster. We have also isolated the pyrophenylphosphonate complex Ag2[PhPO2(O)O2PPh](CH3CN), which exhibits an infinite-chain structure.

  13. Synthesis and Use of a Phosphonate-amidine to Generate an Anti-phosphoarginine Specific Antibody

    PubMed Central

    Subramanian, Venkataraman

    2015-01-01

    Protein arginine phosphorylation is a post-translational modification (PTM) that is important for bacterial growth and virulence. Despite its biological relevance, the intrinsic acid lability of phosphoarginine (pArg) have impaired studies of this novel PTM. Herein, we report for the first time the development of phosphonate-amidines and sulfonate-amidines as isosteres of pArg and then use these mimics as haptens to develop the first high affinity sequence independent anti-pArg specific antibody. Employing this anti-pArg antibody, we further showed that arginine phosphorylation is induced in Bacillus subtilis during oxidative stress. Overall, we expect this antibody to see widespread use in analyzing the biological significance of arginine phosphorylation. Additionally, the chemistry reported here will facilitate the generation of pArg mimetics as highly potent inhibitors of the enzymes that catalyze arginine phosphorylation/dephosphorylation. PMID:26458230

  14. Biosynthesis of rhizocticins, antifungal phosphonate oligopeptides produced by Bacillus subtilis ATCC6633

    PubMed Central

    Borisova, Svetlana A.; Circello, Benjamin T.; Zhang, Jun Kai; van der Donk, Wilfred A.; Metcalf, William W.

    2010-01-01

    Summary Rhizocticins are phosphonate oligopeptide antibiotics containing the C-terminal non-proteinogenic amino acid (Z)-l-2-amino-5-phosphono-3-pentenoic acid (APPA). Here we report the identification and characterization of the rhizocticin biosynthetic gene cluster (rhi) in Bacillus subtilis ATCC6633. Rhizocticin B was heterologously produced in the non-producer strain Bacillus subtilis 168. A biosynthetic pathway is proposed based on bioinformatics analysis of the rhi genes. One of the steps during the biosynthesis of APPA is an unusual aldol reaction between phosphonoacetaldehyde and oxaloacetate catalyzed by an aldolase homolog RhiG. Recombinant RhiG was prepared and the product of an in vitro enzymatic conversion was characterized. Access to this intermediate allows for biochemical characterization of subsequent steps in the pathway. PMID:20142038

  15. Possible use of non-flammable phosphonate ethers as pure electrolyte solvent for lithium batteries

    NASA Astrophysics Data System (ADS)

    Feng, J. K.; Ai, X. P.; Cao, Y. L.; Yang, H. X.

    Dimethyl methyl phosphonate (DMMP) was selected and tested as a non-flammable solvent for primary and secondary lithium batteries, because of its non-flammability, good solvency of lithium salts and appropriate liquidus properties. Experimental results demonstrated that DMMP can solvate considerable amount of commonly used lithium salts to form non-flammable and Li +-conducting electrolyte, which has very wide electrochemical window (>5 V vs. Li) and excellent electrochemical compatibility with metallic lithium anode and oxide cathodes. Primary Li-MnO 2 cells using DMMP-based electrolyte showed almost the same discharge performances as those using organic carbonate electrolytes, and also, Li-LiMn 2O 4 cells using DMMP electrolyte exhibited greatly improved cycleability and dischargeability, suggesting a feasible application of this new electrolyte for constructing high performance and non-flammable lithium batteries.

  16. A report on emergent uranyl binding phenomena by an amidoxime phosphonic acid co-polymer

    DOE PAGES

    Abney, C. W.; Das, S.; Mayes, R. T.; ...

    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

  17. New water-soluble metal working fluids additives from phosphonic acid derivatives for aluminum alloy materials.

    PubMed

    Kohara, Ichitaro; Tomoda, Hideyuki; Watanabe, Shoji

    2007-01-01

    Water-soluble metal working fluids are used for processing of aluminum alloy materials. This short paper describes properties of new additives for water-soluble cutting fluids for aluminum alloy materials. Some alkyldiphosphonic acids were prepared with known method. Amine salts of these phosphonic acids showed anti-corrosion property for aluminum alloy materials. However, they have no hard water tolerance. Monoesters of octylphosphonic acid were prepared by the reaction of octylphosphonic acid dichloride with various alcohols in the presence of triethylamine. Amine salts of monoester of octylphosphonic acid with diethyleneglycol monomethyl ether, ethyleneglycol monomethyl ether and triethyleneglycol monomethyl ether showed both of a good anti-corrosion property for aluminum alloy materials and hard water tolerance.

  18. A report on emergent uranyl binding phenomena by an amidoxime phosphonic acid co-polymer

    SciTech Connect

    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 exposed 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.

  19. Engineering of an industrial polyoxin producer for the rational production of hybrid peptidyl nucleoside antibiotics.

    PubMed

    Zhai, Lipeng; Lin, Shuangjun; Qu, Dongjing; Hong, Xuechuan; Bai, Linquan; Chen, Wenqing; Deng, Zixin

    2012-07-01

    Polyoxins and nikkomycins are potent antifungal peptidyl nucleoside antibiotics, which inhibit fungal cell wall biosynthesis. They consist of a nucleoside core and one or two independent peptidyl moieties attached to the core at different sites. Making mutations and introducing heterologous genes into an industrial Streptomyces aureochromogenes polyoxin producer, resulted in the production of four polyoxin-nikkomycin hybrid antibiotics designated as polyoxin N and nikkoxin B-D, whose structures were confirmed using high resolution MS and NMR. Two of the hybrid antibiotics, polyoxin N and nikkoxin D, were significantly more potent against some human or plant fungal pathogens than their parents. The data provides an example for rational generation of novel peptidyl nucleoside antibiotics in an industrial producer.

  20. 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.

  1. Nucleoside Diphosphatase and 5′-Nucleotidase Activities of Soybean Root Nodules and Other Tissues 1

    PubMed Central

    Doremus, Holly D.; Blevins, Dale G.

    1988-01-01

    Nucleoside diphosphatase and 5′-nucleotidase activities were both found to be very high in extracts of soybean (Glycine max L.) root nodules. Both activities increased early in soybean nodule development, prior to the rise in leghemoglobin, and both were found at equivalent levels in nitrogenfixing and nonfixing nodules. Based on a survey of other tissues, these activities were both highest in soybean nodules (1300 nanomoles per milligram protein per minute, nucleoside diphosphatase and 500 nanomoles per milligram protein per minute, 5′-nucleotidase), but they were not always associated with each other; in some tissues one was high and the other low. Neither activity correlated well with ureide production; both seem, rather, to be primarily involved in some other metabolic function. Both the nucleoside diphosphatase and 5′-nucleotidase of soybean nodules were soluble proteins, and neither appeared to be associated with plastids, mitochondria, or bacteroids. PMID:16666122

  2. Identification of amino acid residues responsible for the pyrimidine and purine nucleoside specificities of human concentrative Na(+) nucleoside cotransporters hCNT1 and hCNT2.

    PubMed

    Loewen, S K; Ng, A M; Yao, S Y; Cass, C E; Baldwin, S A; Young, J D

    1999-08-27

    hCNT1 and hCNT2 mediate concentrative (Na(+)-linked) cellular uptake of nucleosides and nucleoside drugs by human cells and tissues. The two proteins (650 and 658 residues, 71 kDa) are 72% identical in sequence and contain 13 putative transmembrane helices (TMs). When produced in Xenopus oocytes, recombinant hCNT1 is selective for pyrimidine nucleosides (system cit), whereas hCNT2 is selective for purine nucleosides (system cif). Both transport uridine. We have used (i) chimeric constructs between hCNT1 and hCNT2, (ii) sequence comparisons with a newly identified broad specificity concentrative nucleoside transporter (system cib) from Eptatretus stouti, the Pacific hagfish (hfCNT), and (iii) site-directed mutagenesis of hCNT1 to identify two sets of adjacent residues in TMs 7 and 8 of hCNT1 (Ser(319)/Gln(320) and Ser(353)/Leu(354)) that, when converted to the corresponding residues in hCNT2 (Gly(313)/Met(314) and Thr(347)/Val(348)), changed the specificity of the transporter from cit to cif. Mutation of Ser(319) in TM 7 of hCNT1 to Gly enabled transport of purine nucleosides, whereas concurrent mutation of Gln(320) to Met (which had no effect on its own) augmented this transport. The additional mutation of Ser(353) to Thr in TM 8 converted hCNT1/S319G/Q320M, from cib to cif, but with relatively low adenosine transport activity. Additional mutation of Leu(354) to Val (which had no effect on its own) increased the adenosine transport capability of hCNT1/S319G/Q320M/S353T, producing a full cif-type transporter phenotype. On its own, the S353T mutation converted hCNT1 into a transporter with novel uridine-selective transport properties. Helix modeling of hCNT1 placed Ser(319) (TM 7) and Ser(353) (TM 8) within the putative substrate translocation channel, whereas Gln(320) (TM 7) and Leu(354) (TM 8) may exert their effects through altered helix packing.

  3. Step by Step Assembly of Polynuclear Lanthanide Complexes with a Phosphonated Bipyridine Ligand.

    PubMed

    Souri, Nabila; Tian, Pingping; Lecointre, Alexandre; Lemaire, Zoé; Chafaa, Salah; Strub, Jean-Marc; Cianférani, Sarah; Elhabiri, Mourad; Platas-Iglesias, Carlos; Charbonnière, Loïc J

    2016-12-19

    The synthesis of the octadentate ligand L (LH8 = ((([2,2'-bipyridine]-6,6'-diylbis(methylene))bis(azanetriyl))tetrakis(methylene))tetrakis(phosphonic acid)) is reported. The coordination of L with various lanthanide cations was monitored by absorption and luminescence spectrophotometric titration experiments (Ln = Tb, Yb), potentiometry (Ln = La, Eu, Lu), and mass spectrometry (Ln = Tb). It was found that L forms very stable mononuclear (LnL) species in aqueous solutions (log K = 19.80(5), 19.5(2), and 19.56(5) for La, Eu, and Lu, respectively) with no particular trend along the series. Spectroscopic data showed the Ln cations to be enclosed in the cavity formed by the octadentate ligand, thereby shielding the metal from interactions with water molecules in the first coordination sphere. When more than one equivalent of cations is added, the formation of polynuclear [(LnL)2Lnx] complexes (x = 1-3) can be observed, the presence of which could be confirmed by electrospray and MALDI mass spectrometry experiments. DFT modeling of the mononuclear (LnL) complexes indicated that the coordination of the cation in the cavity of the ligand results in a very asymmetric charge distribution, with a region of small negative electrostatic potential on the hemisphere composed of the chromophoric bipyridyl moiety and an electron-rich domain at the opposite hemisphere around the four phosphonate functions. DFT further showed that this polarization is most likely at the origin of the strong interactions between the (LnL) complexes and the incoming additional cations, leading to the formation of the polynuclear species. (1)H and (31)P NMR were used to probe the possible exchange of the lanthanide complexed in the cavity of the ligand in D2O, revealing no detectable exchange after 4 weeks at 80 °C and neutral pD, therefore pointing out an excellent kinetic inertness.

  4. Stereoselective Synthesis of 4-Substituted Cyclic Sulfamidate-5-Phosphonates by Using Rh-Catalyzed, Asymmetric Transfer Hydrogenation with Accompanying Dynamic Kinetic Resolution.

    PubMed

    Seo, Yeon Ji; Kim, Jin-ah; Lee, Hyeon-Kyu

    2015-09-04

    Dynamic kinetic resolution driven, asymmetric transfer hydrogenation of 4-substituted cyclic sulfamidate imine-5-phosphonates produces the corresponding cyclic sulfamidate-5-phosphonates. The process employs a HCO2H/Et3N mixture as the hydrogen source and the chiral Rh catalysts, (R,R)- or (S,S)-Cp*RhCl(TsDPEN), and it takes place at room temperature within 1 h with high yields and high levels of stereoselectivity.

  5. Vectorial transport of nucleoside analogs from the apical to the basolateral membrane in double-transfected cells expressing the human concentrative nucleoside transporter hCNT3 and the export pump ABCC4.

    PubMed

    Rius, Maria; Keller, Daniela; Brom, Manuela; Hummel-Eisenbeiss, Johanna; Lyko, Frank; Keppler, Dietrich

    2010-07-01

    The identification of the transport proteins responsible for the uptake and the efflux of nucleosides and their metabolites enables the characterization of their vectorial transport and a better understanding of their absorption, distribution, and elimination. Human concentrative nucleoside transporters (hCNTs/SLC28A) are known to mediate the transport of natural nucleosides and some nucleoside analogs into cells in a sodium-dependent and unidirectional manner. On the other hand, several human multidrug resistance proteins [human ATP-binding cassette transporter, subfamily C (ABCC)] cause resistance against nucleoside analogs and mediate transport of phosphorylated nucleoside derivatives out of the cells in an ATP-dependent manner. For the integrated analysis of uptake and efflux of these compounds, we established a double-transfected Madin-Darby canine kidney (MDCK) II cell line stably expressing the human uptake transporter hCNT3 in the apical membrane and the human efflux pump ABCC4 in the basolateral membrane. The direction of transport was from the apical to the basolateral compartment, which is in line with the unidirectional transport and the localization of both recombinant proteins in the MDCKII cells. Recombinant hCNT3 mediated the transport of several known nucleoside substrates, and we identified 5-azacytidine as a new substrate for hCNT3. It is of interest that coexpression of both transporters was confirmed in pancreatic adenocarcinomas, which represent an important clinical indication for the therapeutic use of nucleoside analogs. Thus, our results establish a novel cell system for studies on the vectorial transport of nucleosides and their analogs from the apical to the basolateral compartment. The results contribute to a better understanding of the cellular transport characteristics of nucleoside drugs.

  6. A sample preparation protocol for quantification of radiolabeled nucleoside incorporation into DNA by accelerator mass spectrometry

    NASA Astrophysics Data System (ADS)

    Hah, Sang Soo; Mundt, Janna M.; Ubick, Esther A.; Turteltaub, Kenneth W.; Gregg, Jeff P.; Henderson, Paul T.

    2007-06-01

    A general protocol is described for measuring the incorporation of radiocarbon-labeled 2‧-deoxynucleosides into DNA using accelerator mass spectrometry (AMS). This technology provides attomole (10-18 mol) sensitivity, with detection limits for DNA analysis in the range of one 14C atom per 1011-1012 total carbons. In practice this corresponds to approximately 1 labeled nucleoside per 1011 normal bases. A key aspect of the method is the use of precautions aimed at prevention of artifactual DNA oxidation during the sample preparation by the use of antioxidants and chaotropic salts during the DNA isolation. In principle, any type of appropriately labeled nucleoside derivative can be studied using the described protocol, provided that there is incorporation of the deoxynucleoside into DNA. We demonstrated this protocol using MCF-7 human breast cancer cells and a mouse model for mammary carcinoma, which we dosed with 14C-labeled 2‧-deoxyguanosine (dG) and 14C-labeled 7,8-dihydro-8-oxo-2‧-deoxyguanosine (8-oxodG). The nucleoside 8-oxodG is a ubiquitous compound that forms in cells by the reaction of dG with reactive oxygen species which has been associated with numerous disease, carcinogenesis and aging. DNA from cells treated with 14C-labeled nucleosides was isolated and prepared for analysis by AMS in order to measure the DNA-bound radioactivity. The method allows the generation of reliable and sufficient yields of pure DNA from human cells and animal tissues for analysis of radiocarbon levels. Ultimately, this protocol will be applied to understanding the role of modified nucleoside incorporation into DNA in cancer initiation and progression, but could also be used to study any DNA metabolism process where 14C-labeled nucleosides are used.

  7. 6-Methylpurine derived sugar modified nucleosides: Synthesis and evaluation of their substrate activity with purine nucleoside phosphorylases.

    PubMed

    Hassan, Abdalla E A; Abou-Elkhair, Reham A I; Parker, William B; Allan, Paula W; Secrist, John A

    2016-04-01

    6-Methylpurine (MeP) is cytotoxic adenine analog that does not exhibit selectivity when administered systemically, and could be very useful in a gene therapy approach to cancer treatment involving Escherichia coli PNP. The prototype MeP releasing prodrug, 9-(β-d-ribofuranosyl)-6-methylpurine, MeP-dR has demonstrated good activity against tumors expressing E. coli PNP, but its antitumor activity is limited due to toxicity resulting from the generation of MeP from gut bacteria. Therefore, we have embarked on a medicinal chemistry program to identify non-toxic MeP prodrugs that could be used in conjunction with E. coli PNP. In this work, we report on the synthesis of 9-(6-deoxy-β-d-allofuranosyl)-6-methylpurine (3) and 9-(6-deoxy-5-C-methyl-β-d-ribo-hexofuranosyl)-6-methylpurine (4), and the evaluation of their substrate activity with several phosphorylases. The glycosyl donors; 1,2-di-O-acetyl-3,5-di-O-benzyl-α-d-allofuranose (10) and 1-O-acetyl-3-O-benzyl-2,5-di-O-benzoyl-6-deoxy-5-C-methyl-β-d-ribohexofuran-ose (15) were prepared from 1,2:5,6-di-O-isopropylidine-α-d-glucofuranose in 9 and 11 steps, respectively. Coupling of 10 and 15 with silylated 6-methylpurine under Vorbrüggen glycosylation conditions followed conventional deprotection of the hydroxyl groups furnished 5'-C-methylated-6-methylpurine nucleosides 3 and 4, respectively. Unlike 9-(6-deoxy-α-l-talo-furanosyl)-6-methylpurine, which showed good substrate activity with E. coli PNP mutant (M64V), the β-d-allo-furanosyl derivative 3 and the 5'-di-C-methyl derivative 4 were poor substrates for all tested glycosidic bond cleavage enzymes.

  8. Synthesis of novel homo-N-nucleoside analogs composed of a homo-1,4-dioxane sugar analog and substituted 1,3,5-triazine base equivalents.

    PubMed

    Yu, Qiang; Schwidom, Dirk; Exner, Alexander; Carlsen, Per

    2008-12-10

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

  9. Highly selective capture of nucleosides with boronic acid functionalized polymer brushes prepared by atom transfer radical polymerization.

    PubMed

    Cheng, Ting; Zhu, Shuqiang; Zhu, Bin; Liu, Xiaoyan; Zhang, Haixia

    2016-04-01

    The nucleoside or modified nucleoside level in biological fluids reflects the pathological or physiological state of the body. Boronate affinity absorbents are widely used to selectively extract nucleosides from complex samples. In this work, a novel functionalized absorbent was synthesized by attaching 4-mercaptophenylboronic acid to gold nanoparticles on modified attapulgite. The surface of the attapulgite was modified by poly(acryloyloxyethyltrimethyl ammonium chloride) by atom transfer radical polymerization, creating many polymer brushes on the surface. The resultant material exhibited superior binding capacity (30.83 mg/g) for adenosine and was able to capture cis-diol nucleosides from 1000-fold interferences. Finally, to demonstrate its potential for biomolecule extraction, this boronate affinity material was used to preconcentrate nucleosides from human urine and plasma.

  10. An efficient preparation of isosteric phosphonate analogues of sphingolipids by opening of oxirane and cyclic sulfamidate intermediates with alpha-lithiated alkylphosphonic esters.

    PubMed

    Sun, Chaode; Bittman, Robert

    2004-10-29

    D-erythro-(2S,3R,4E)-Sphingosine-1-phosphonate (1), the isosteric phosphonate analogue of naturally occurring sphingosine 1-phosphate (1a), and D-ribo-phytosphingosine 1-phosphonate (2), the isosteric phosphonate analogue of D-ribo-phytosphingosine-1-phosphate (2a), were synthesized starting with methyl 2,3-O-isopropylidene-d-glycerate (4) and D-ribo-phytosphingosine (3), respectively. Oxirane 12 was formed in eight steps from 4, and cyclic sulfamidate 22 was formed in five steps from 3. The phosphonate group was introduced via regioselective ring-opening reactions of oxirane 12 and cyclic sulfamidate 22 with lithium dialkyl methylphosphonate, affording 13 and 23, respectively. The synthesis of 1 was completed by S(N)2 displacement of chloromesylate intermediate 14b with azide ion, followed by conversion of the resulting azido group to a NHBoc group and deprotection. The synthesis of 2 was completed by cleavage of the acetal, N-benzyl, and alkyl phosphonate ester groups.

  11. Tailored control and optimisation of the number of phosphonic acid termini on phosphorus-containing dendrimers for the ex-vivo activation of human monocytes.

    PubMed

    Rolland, Olivier; Griffe, Laurent; Poupot, Mary; Maraval, Alexandrine; Ouali, Armelle; Coppel, Yannick; Fournié, Jean-Jacques; Bacquet, Gérard; Turrin, Cédric-Olivier; Caminade, Anne-Marie; Majoral, Jean-Pierre; Poupot, Rémy

    2008-01-01

    The syntheses of a series of phosphonic acid-capped dendrimers is described. This collection is based on a unique set of dendritic structural parameters-cyclo(triphosphazene) core, benzylhydrazone branches and phosphonic acid surface-and was designed to study the influence of phosphonate (phosphonic acid) surface loading towards the activation of human monocytes ex vivo. Starting from the versatile hexachloro-cyclo(triphosphazene) N(3)P(3)Cl(6), six first-generation dendrimers were obtained, bearing one to six full branches, that lead to 4, 8, 12, 16, 20 and 24 phosphonate termini, respectively. The surface loading was also explored at the limit of dense packing by means of a first-generation dendrimer having a cyclo(tetraphosphazene) core and bearing 32 termini, and with a first-generation dendrimer based on a AB(2)/CD(5) growing pattern and bearing 60 termini. Human monocyte activation by these dendrimers confirms the requirement of the whole dendritic structure for bioactivity and identifies the dendrimer bearing four branches, thus 16 phosphonate termini, as the most bioactive.

  12. In situ enzymatic removal of orthophosphate by the nucleoside phosphorylase catalyzed phosphorolysis of nicotinamide riboside.

    PubMed

    Shriver, J W; Sykes, B D

    1982-09-01

    An enzymatic orthophosphate removal system is described which can be effectively used to continuously remove orthophosphate from biochemical samples. The phosphorolysis of nicotinamide riboside is catalyzed by calf spleen nucleoside phosphorylase to give ribose-1-PO4 and nicotinamide along with a proton. At pH 8 the production of ribose-1-PO4 from orthophosphate is essentially quantitative. This reaction can be monitored optically or by 31P nuclear magnetic resonance (NMR). Equations are given for determining the time required to remove a given amount of phosphate from a typical NMR sample with a known amount of nucleoside phosphorylase. The effects of a competing orthophosphate-producing reaction are considered.

  13. GS-5734 and its parent nucleoside analog inhibit Filo-, Pneumo-, and Paramyxoviruses

    PubMed Central

    Lo, Michael K.; Jordan, Robert; Arvey, Aaron; Sudhamsu, Jawahar; Shrivastava-Ranjan, Punya; Hotard, Anne L.; Flint, Mike; McMullan, Laura K.; Siegel, Dustin; Clarke, Michael O.; Mackman, Richard L.; Hui, Hon C.; Perron, Michel; Ray, Adrian S.; Cihlar, Tomas; Nichol, Stuart T.; Spiropoulou, Christina F.

    2017-01-01

    GS-5734 is a monophosphate prodrug of an adenosine nucleoside analog that showed therapeutic efficacy in a non-human primate model of Ebola virus infection. It has been administered under compassionate use to two Ebola patients, both of whom survived, and is currently in Phase 2 clinical development for treatment of Ebola virus disease. Here we report the antiviral activities of GS-5734 and the parent nucleoside analog across multiple virus families, providing evidence to support new indications for this compound against human viruses of significant public health concern. PMID:28262699

  14. [Substrate specificity and kinetic properties of a soluble nucleoside triphosphatase from bovine kidneys].

    PubMed

    Sivuk, V F; Rusina, I M; Luchko, T A; Makarchikov, A F

    2008-01-01

    Soluble nucleoside triphosphatase differing in its properties from all known proteins with NTPase activity was partially purified from bovine kidneys. The enzyme has pH optimum of 7.5, molecular mass of 60 kDa, as estimated by gel chromatography, and shows an absolute dependence on divalent metal ions. NTPase obeyed Michaelis-Menten kinetics in the range of substrate concentration tested from 45 to 440 microM; the apparent Km for inosine-5'-triphosphate was calculated to be 23.3 microM. The enzyme was found to possess a broad substrate specificity, being capable of hydrolyzing various nucleoside-5'-tri- as well as diphosphates.

  15. Fluorescent nucleosides with 'on-off' switching function, pH-responsive fluorescent uridine derivatives.

    PubMed

    Saito, Yoshio; Miyamoto, Shigenori; Suzuki, Azusa; Matsumoto, Katsuhiko; Ishihara, Tsutomu; Saito, Isao

    2012-04-15

    We synthesized various pH-responsive fluorescent deoxyuridine derivatives (1a-g). These fluorescent nucleosides exhibited distinctive fluorescence at 470-600 nm in aqueous solvents containing methanol only at acidic to neutral pH values. In particular, 1f exhibited strong fluorescence only at pH range of 3.1-7.2 with a pK(a) of 6.1. Such pH-sensitive fluorescent nucleosides can be used as 'on-off' fluorescence switch for monitoring pH change in biological systems, particularly for cancer cell detection.

  16. Biotransformation of 2,6-diaminopurine nucleosides by immobilized Geobacillus stearothermophilus.

    PubMed

    De Benedetti, Eliana C; Rivero, Cintia W; Britos, Claudia N; Lozano, Mario E; Trelles, Jorge A

    2012-01-01

    An efficient and green bioprocess to obtain 2,6-diaminopurine nucleosides using thermophilic bacteria is herein reported. Geobacillus stearothermophilus CECT 43 showed a conversion rate of 90 and 83% at 2 h to obtain 2,6-diaminopurine-2'-deoxyriboside and 2,6-diaminopurine riboside, respectively. The selected biocatalyst was successfully stabilized in an agarose matrix and used to produce up to 23.4 g of 2,6-diaminopurine-2'-deoxyriboside in 240 h of process. These nucleoside analogues can be used as prodrug precursors or in antisense oligonucleotide synthesis.

  17. Recent advances on the enantioselective synthesis of C-nucleosides inhibitors of inosine monophosphate dehydrogenase (IMPDH).

    PubMed

    Merino, Pedro; Ghirardello, Mattia; Tejero, Tomas; Delso, Ignacio; Matute, Rosa

    2014-01-01

    This review will describe the recent advances in the synthesis of C-nucleosides with inhibitory activity of inosine monophosphate dehydrogenase (IMPDH), a key enzyme in the biosynthesis of guanine nucleotides. The review will cover synthetic approaches of structural analogues showing modifications in the furanose ring as well as in the heterocyclic base. Heterocyclic sugar nucleoside analogues in which the furanose ring has been replaced by a different heterocyclic ring including aza analogues, thioanalogues as well as dioxolanyl and isoxazolidinyl analogues are also considered.

  18. 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.

  19. 4-Azido-2-pyrimidinone Nucleosides and Related Chemistry.

    PubMed

    Kotra, Lakshmi P.; Wang, PingPing; Bartlett, Michael G.; Shanmuganathan, Kirupa; Xu, Zusheng; Cavalcanti, Sócrates; Newton, M. Gary; Chu, Chung K.

    1997-10-17

    As a part of azide prodrug approach, we synthesized a 4-azido analog of ara-C (4) as a prodrug for ara-C. The compound 4 was obtained from 1-(beta-D-arabinofuranosyl)uracil (1) in three steps. At pH 7.0 and 11.0, a loss of UV absorption of the compound 4 was observed resulting from a transformation that was proved by identifying the transformed product 5 by 1-D, and 2-D NMR as well as tandem mass spectral studies. In NMR studies, changes in the chemical shifts were observed at positions 5, 6, 1', and 2' between the compounds 4 and 5. A molecular peak at m/z 270.1 (MH(+)) was observed in the mass spectra of compounds 4 and the transformed product 5. A fragment at 180.2 was identified to be the compound 6, containing the 6,2'-anhydro linkage of compound 5. The X-ray analysis indicated that compound 4 exists as 1-(beta-D-arabinofuranosyl)tetrazolo[4,5-c]pyrimidin-2-one, with the azide moiety cyclized. To understand if the chemical instability of the nucleoside 4 was due to the arabino configuration of 2'-OH or due to the azido moiety, we also studied 1-(2,3-dideoxy-2-fluoro-beta-D-arabinofuranosyl)tetrazolo[4,5-c]pyrimidin-2-one (11) and 4-azido-1-methyl-2-pyrimidinone (15). At pH 2.0 and 7.0, similar UV profiles were observed for compounds 11 and 15. However, at pH 11.0, lambda(max) shifted slowly to lower wavelength for both compounds 11 and 15. In a separate kinetic study, they were stable at pH 7.4 for up to 2.45 h. From the NMR and high-resolution mass spectral studies, it was concluded that in the presence of ammonium hydroxide, an addition of amine occurred at 6-position of compound 11. Thus, the stability profiles of compounds 4, 11, and 15 were different. The instability and the formation of 2',6-anhydro bond in compound 4 in nonacidic media was due to the presence of 2'-OH in the arabino configuration and probably not due to the azide group.

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

    SciTech Connect

    Scheuerman, R.A.

    1992-01-01

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

  1. 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.

  2. The role of minerals in the thermal alteration of organic matter. IV - Generation of n-alkanes, acyclic isoprenoids, and alkenes in laboratory experiments

    NASA Astrophysics Data System (ADS)

    Huizinga, Bradley J.; Tannenbaum, Eli; Kaplan, Isaac R.

    1987-05-01

    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.

  3. Asymmetric Copper-Catalyzed Vinylogous Mukaiyama Michael Addition of Cyclic Dienol Silanes to Unsaturated α-Keto Phosphonates.

    PubMed

    Steinkamp, Anne-Dorothee; Frings, Marcus; Thomé, Isabelle; Schiffers, Ingo; Bolm, Carsten

    2015-05-18

    A highly stereoselective vinylogous Mukaiyama Michael reaction (VMMR) leading to α-keto phosphonate-containing γ-butenolides with two stereogenic centers is described. The presented transformation is catalyzed by a combination of a commercially available C2 -symmetric bisoxazoline (BOX) ligand and a copper salt and tolerates a variety of nucleophiles and electrophiles. The stereoselectivities of the reactions are good to excellent and the products are obtained in moderate to high yields.

  4. 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

  5. Direct C-H difluoromethylenephosphonation of arenes and heteroarenes with bromodifluoromethyl phosphonate via visible-light photocatalysis.

    PubMed

    Wang, Lin; Wei, Xiao-Jing; Lei, Wen-Long; Chen, Han; Wu, Li-Zhu; Liu, Qiang

    2014-12-28

    This communication reports a room temperature visible-light-driven protocol for the C-H difluoromethylenephosphonation of arenes and heteroarenes. Using commercially available diethyl bromodifluoromethyl phosphonate as a precursor of difluoromethyl radical, fac-Ir(ppy)3 as a photosensitizer and a 3 W blue LED as a light source, an array of aromatic compounds containing difluoromethylenephosphonyl groups were prepared directly from the corresponding arenes and heteroarenes in excellent to moderate yields.

  6. Substituted ethan phosphonic acid esters as reagents for the separation of molybdenum from rhenium by solvent extraction.

    PubMed

    Jordanov, N; Mareva, S; Borisov, G; Jordanov, B

    1968-02-01

    New esters of the ethan phosphonic acids have been synthesized and their extraction properties studied with respect to Mo(VI), Re(VII), Fe(III),Au(III),Tl(III) and Sb(V). A possibility is shown for the analytical separation of molybdenum from rhenium (beta = 700). The state of these new extraction agents in carbon tetrachloride solution, and the mechanism of the extraction processes, have been investigated by means of infrared spectra.

  7. Solid state {sup 31}P NMR study of phosphonate binding sites in guanidine-functionalized, molecular imprinted silica xerogels

    SciTech Connect

    Sasaki, D.Y.; Alam, T.D.

    2000-01-03

    Phosphonate binding sites in guanidine and ammonium surface-functionalized silica xerogels were prepared via the molecular imprinting technique and characterized using solid state {sup 31}P MAS NMR. One-point, two-point, and non-specific host-guest interactions between phenylphosphonic acid (PPA) and the functionalized gels were distinguished by characteristic chemical shifts of the observed absorption peaks. Using solid state as well as solution phase NMR analyses, absorptions observed at 15.5 ppm and 6.5 ppm were identified as resulting from the 1:1 (one-point) and 2:1 (two-point) guanidine to phosphonate interactions, respectively. Similar absorptions were observed with the ammonium functionalized gels. By examining the host-guest interactions within the gels, the efficiency of the molecular imprinting procedure with regard to the functional monomer-to-template interaction could be readily assessed. Template removal followed by substrate adsorption studies conducted on the guanidine functionalized gels provided a method to evaluate the binding characteristics of the receptor sites to a phosphonate substrate. During these experiments, {sup 29}Si and {sup 31}P MAS NMR acted as diagnostic monitors to identify structural changes occurring in the gel matrix and at the receptor site from solvent mediated processes.

  8. 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

  9. 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.

  10. Comparative genomic analysis of equilibrative nucleoside transporters suggests conserved protein structure despite limited sequence identity.

    PubMed

    Sankar, Narendra; Machado, Jerry; Abdulla, Parween; Hilliker, Arthur J; Coe, Imogen R

    2002-10-15

    Equilibrative nucleoside transporters (ENTs) are a recently characterized and poorly understood group of membrane proteins that are important in the uptake of endogenous nucleosides required for nucleic acid and nucleoside triphosphate synthesis. Despite their central importance in cellular metabolism and nucleoside analog chemotherapy, no human ENT gene has been described and nothing is known about gene structure and function. To gain insight into the ENT gene family, we used experimental and in silico comparative genomic approaches to identify ENT genes in three evolutionarily diverse organisms with completely (or almost completely) sequenced genomes, Homo sapiens, Caenorhabditis elegans and Drosophila melanogaster. We describe the chromosomal location, the predicted ENT gene structure and putative structural topologies of predicted ENT proteins derived from the open reading frames. Despite variations in genomic layout and limited ortholog protein sequence identity (< or =27.45%), predicted topologies of ENT proteins are strikingly similar, suggesting an evolutionary conservation of a prototypic structure. In addition, a similar distribution of protein domains on exons is apparent in all three taxa. These data demonstrate that comparative sequence analyses should be combined with other approaches (such as genomic and proteomic analyses) to fully understand structure, function and evolution of protein families.

  11. Non-nucleoside structures retain full anti-HCMV potency of the dideoxy furanopyrimidine family.

    PubMed

    Bidet, Olivier; McGuigan, Christopher; Snoeck, Robert; Andrei, Graciela; De Clercq, Erik; Balzarini, Jan

    2004-11-01

    We have recently reported that 2',3'dideoxy analogues of our exquisitely potent anti-VZV furanopyrimidine deoxynucleosides are shifted to selective anti-HCMV agents. We now find that the fully deoxygenated 2',3',5'-trideoxy analogue is fully antivirally active. This is taken as proof that these agents act by a novel non-nucleoside mechanism of action.

  12. Synthesis and anti-HIV activity of novel cyclopentenyl nucleoside analogues of 8-azapurine.

    PubMed

    Canoa, Pilar; González-Moa, María J; Teijeira, Marta; Terán, Carmen; Uriarte, Eugenio; Pannecouque, Christophe; De Clercq, Erik

    2006-10-01

    Novel nucleoside analogues of structure 3-5 were synthesized starting from (+/-)-cis-2-amino-3-cyclopentenylmethanol (1). The chlorine derivative 3 inhibited both HIV-1 and HIV-2 replication in MT-4 cells with IC(50) values of 10.67 microM and of 13.79 microM, respectively.

  13. Thermostability of mammalian brain ribosomes and the effects of nucleoside triphosphates on their heat-sensitivity.

    PubMed

    Grove, B K; Johnson, T C; Gilbert, B E

    1974-02-01

    Mammalian brain ribosomes were found to be heat-labile. On preincubation of the ribosomes at 37 degrees C, their ability to participate in polypeptide-synthesis reactions was substantially diminished. Despite the sensitivity of ribosomal protein synthesis to heat-inactivation, preincubation resulted in no significant alterations in ribosomal sedimentation profiles or changes in the integrity of the ribosomal RNA. The thermolability of brain ribosomes was shown to be associated with their inability to bind both template RNA and aminoacyl-tRNA. Similar experiments with brain ribosomal subunits demonstrated that the small (40S) subunit was more sensitive to heat-inactivation than the large (60S) subunit. The presence of ATP (1mm) protected ribosomes from thermal inactivation, although this protection was shown to be temporary. The protection appeared to be specific to nucleoside triphosphates, since GTP and UTP also stabilized ribosomes to thermal denaturation whereas nucleoside diphosphates (ADP) and nucleoside monophosphates (AMP and cyclic AMP) did not alter ribosomal sensitivity to heat. Although 1mm concentrations of nucleoside triphosphates protected ribosomes from heat-inactivation, the presence of higher concentrations resulted in complete inactivation of ribosomal activity.

  14. 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)

  15. 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.

  16. A nucleoside triphosphate-dependent deoxyribonuclease from Bacillus laterosporus. Purification and characterization of the enzyme.

    PubMed

    Anai, M; Mihara, T; Yamanaka, M; Shibata, T; Takagi, Y

    1975-07-01

    A deoxyribonuclease, which requires nucleoside triphosphate for reaction, has been purified about 150-fold from extracts of Bacillus laterosporus. Potassium phosphate and ethylene glycol stabilize the purified enzyme. The enzyme degrades double-stranded DNA about 100 times faster than heat-denatured DNA in the presence of nucleoside triphosphate. Double-stranded DNA is not degraded to any measurable extent in the absence of ATP, but the enzyme exhibits activity toward denatured DNA in the absence of nucleoside triphosphate, and this activity seems to be an intrinsic property of this enzyme protein. The optimum pH is 8.5 and the maximum activity is obtained in the copresence of Mg2+ (8.0 X 10(-3)M) and Mn2+ (7.0 X 10(-5)M). ATP and dATP are most effective and nucleoside di- or monophosphates are ineffective. ATP is converted to ADP and inorganic phosphate during the reaction and the ratio of the amount of ATP cleaved to that of hydrolyzed phosphodiester bonds of DNA is about 3:1. An inhibitor of the enzyme was observed in bacterial extracts prepared by sonic disruption; the inhibitory substance is produced in the bacteria in the later stages of cell growth. Preliminary results show that the inhibitor emerged near the void volume of a Sephadex G-200 column, and was relatively heat-stable, RNase-resistant, and DNase-sensitive.

  17. Aspartic acid based nucleoside phosphoramidate prodrugs as potent inhibitors of hepatitis C virus replication.

    PubMed

    Maiti, Munmun; Maiti, Mohitosh; Rozenski, Jef; De Jonghe, Steven; Herdewijn, Piet

    2015-05-14

    In view of a persistent threat to mankind, the development of nucleotide-based prodrugs against hepatitis C virus (HCV) is considered as a constant effort in many medicinal chemistry groups. In an attempt to identify novel nucleoside phosphoramidate analogues for improving the anti-HCV activity, we have explored, for the first time, aspartic acid (Asp) and iminodiacetic acid (IDA) esters as amidate counterparts by considering three 2'-C-methyl containing nucleosides, 2'-C-Me-cytidine, 2'-C-Me-uridine and 2'-C-Me-2'-fluoro-uridine. Synthesis of these analogues required protection for the vicinal diol functionality of the sugar moiety and the amino group of the cytidine nucleoside to regioselectively perform phosphorylation reaction at the 5'-hydroxyl group. Anti-HCV data demonstrate that the Asp-based phosphoramidates are ∼550 fold more potent than the parent nucleosides. The inhibitory activity of the Asp-ProTides was higher than the Ala-ProTides, suggesting that Asp would be a potential amino acid candidate to be considered for developing novel antiviral prodrugs.

  18. PenPC: A Two-step Approach to Estimate the Skeletons of High Dimensional Directed Acyclic Graphs

    PubMed Central

    Ha, Min Jin; Sun, Wei; Xie, Jichun

    2015-01-01

    Summary Estimation of the skeleton of a directed acyclic graph (DAG) is of great importance for understanding the underlying DAG and causal e ects can be assessed from the skeleton when the DAG is not identifiable. We propose a novel method named PenPC to estimate the skeleton of a high-dimensional DAG by a two-step approach. We first estimate the non-zero entries of a concentration matrix using penalized regression, and then fix the difference between the concentration matrix and the skeleton by evaluating a set of conditional independence hypotheses. For high dimensional problems where the number of vertices p is in polynomial or exponential scale of sample size n, we study the asymptotic property of PenPC on two types of graphs: traditional random graphs where all the vertices have the same expected number of neighbors, and scale-free graphs where a few vertices may have a large number of neighbors. As illustrated by extensive simulations and applications on gene expression data of cancer patients, PenPC has higher sensitivity and specificity than the state-of-the-art method, the PC-stable algorithm. PMID:26406114

  19. 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

  20. 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

  1. Octahedral rhodium(III) complexes as kinase inhibitors: Control of the relative stereochemistry with acyclic tridentate ligands.

    PubMed

    Mollin, Stefan; Riedel, Radostan; Harms, Klaus; Meggers, Eric

    2015-07-01

    Octahedral metal complexes are attractive structural templates for the design of enzyme inhibitors as has been demonstrated, for example, with the development of metallo-pyridocarbazoles as protein kinase inhibitors. The octahedral coordination sphere provides untapped structural opportunities but at the same time poses the drawback of dealing with a large number of stereoisomers. In order to address this challenge of controlling the relative metal-centered configuration, the synthesis of rhodium(III) pyridocarbazole complexes with facially coordinating acyclic tridentate ligands was investigated. A strategy for the rapid synthesis of such complexes is reported, the diastereoselectivities of these reactions were investigated, the structure of several complexes were determined by X-ray crystallography, the high kinetic stability of such complexes in thiol-containing solutions was demonstrated in (1)H-NMR experiments, and the protein kinase inhibition ability of this class of complexes was confirmed. It can be concluded that the use of multidentate ligands is currently maybe the most practical strategy to avoid a large number of possible stereoisomers in the course of exploiting octahedral coordination spheres as structural templates for the design of bioactive molecules.

  2. Flaviviridae viruses use a common molecular mechanism to escape nucleoside analogue inhibitors.

    PubMed

    Valdés, James J; Butterill, Philip T; Růžek, Daniel

    2017-03-18

    The RNA-dependent RNA polymerases of Flaviviridae viruses are crucial for replication. The Flaviviridae polymerase is organized into structural motifs (A-G), with motifs F, A, C and E containing interrogating, priming and catalytic substrate-interacting sites. Modified nucleoside analogues act as antiviral drugs by targeting Flaviviridae polymerases and integrating into the synthesized product causing premature termination. A threonine mutation of a conserved serine residue in motif B of Flaviviridae polymerases renders resistance to 2'-C-methylated nucleoside analogues. The mechanism how this single mutation causes Flaviviridae viruses to escape nucleoside analogues is not yet known. Given the pivotal position of the serine residue in motif B that supports motif F, we hypothesized the threonine mutation causes alterations in nucleoside exploration within the entry tunnel. Implementing a stochastic molecular software showed the all-atom 2'-C-methylated analogue reaction within the active sites of wild type and serine-threonine mutant polymerases from Hepacivirus and Flavivirus. Compared with the wild type, the serine-threonine mutant polymerases caused a significant decrease of analogue contacts with conserved interrogating residues in motif F and a displacement of metal ion cofactors. The simulations significantly showed that during the analogue exploration of the active site the hydrophobic methyl group in the serine-threonine mutant repels water-mediated hydrogen bonds with the 2'-C-methylated analogue, causing a concentration of water-mediated bonds at the substrate-interacting sites. Collectively, the data are an insight into a molecular escape mechanism by Flaviviridae viruses from 2'-C-methylated nucleoside analogue inhibitors.

  3. 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

  4. Effects of radiation, acid, and base on the extractant dihexyl-(diethylcarbamoyl)methyl) phosphonate

    SciTech Connect

    Bahner, C.T.; Shoun, R.R.; McDowell, W.J.

    1981-11-01

    The effects of exposure to gamma radiation (/sup 60/Co) and of contact with acidic and basic aqueous solutions on dihexyl((diethylcarbamoyl)methyl)phosphonate (DHDECMP) were studied. Gamma radiation decomposes DHDECMP into a variety of products. The most troublesome of those are the acidic compounds that cause problems in stripping the actinides and lanthanides from the extractant at low acid concentrations. The rate of degradation of DHDECMP by radiation is about the same or only slightly higher than that of tri-n-butyl phosphate (TBP). It is relatively easy to remove the radiation-produced impurities by equilibration (scrubbing) with sodium carbonate or sodium hydroxide or by column chromatographic methods. The hydrolysis of DHDECMP in contact with aqueous solutions containing less than 3 M HNO/sub 3/ is not more severe than that of TBP under the same conditions but is significant above that acid concentration. Hydrolysis of DHDECMP in contact with aqueous sodium hydroxide solution does occur, but it should not pose an important problem with the short contact times such as those anticipated for the removal of the radiation-induced degradation products by caustic scrubbing. Results of various chromatographic tests to characterize the degradation products of DHDECMP are also given.

  5. A Metabolically-Stabilized Phosphonate Analog of Lysophosphatidic Acid Attenuates Collagen-Induced Arthritis

    PubMed Central

    Sevastou, Ioanna; Sirioti, Ivi; Samiotaki, Martina; Madan, Damian; Prestwich, Glenn D.; Aidinis, Vassilis

    2013-01-01

    Rheumatoid arthritis (RA) is a destructive arthropathy with systemic manifestations, characterized by chronic synovial inflammation. Under the influence of the pro-inflammatory milieu synovial fibroblasts (SFs), the main effector cells in disease pathogenesis become activated and hyperplastic while releasing a number of signals that include pro-inflammatory factors and tissue remodeling enzymes. Activated RA SFs in mouse or human arthritic joints express significant quantities of autotaxin (ATX), a lysophospholipase D responsible for the majority of lysophosphatidic acid (LPA) production in the serum and inflamed sites. Conditional genetic ablation of ATX from SFs resulted in attenuation of disease symptoms in animal models, an effect attributed to diminished LPA signaling in the synovium, shown to activate SF effector functions. Here we show that administration of 1-bromo-3(S)-hydroxy-4-(palmitoyloxy)butyl-phosphonate (BrP-LPA), a metabolically stabilized analog of LPA and a dual function inhibitor of ATX and pan-antagonist of LPA receptors, attenuates collagen induced arthritis (CIA) development, thus validating the ATX/LPA axis as a novel therapeutic target in RA. PMID:23923032

  6. Proton-Electron Double-Resonance Imaging of pH using phosphonated trityl probe

    PubMed Central

    Takahashi, Wataru; Bobko, Andrey A.; Dhimitruka, Ilirian; Hirata, Hiroshi; Zweier, Jay L.; Samouilov, Alexandre

    2014-01-01

    Variable Radio Frequency Proton-Electron Double-Resonance Imaging (VRF PEDRI) enables extracting a functional map from a limited number of images acquired at pre-selected EPR frequencies using specifically designed paramagnetic probes with high quality spatial resolution and short acquisition times. In this work we explored potential of VRF PEDRI for pH mapping of aqueous samples using recently synthesized pH-sensitive phosphonated trityl radical, pTR. The ratio of Overhauser enhancements measured at each pixel at two different excitation frequencies corresponding to the resonances of protonated and deprotonated forms of pTR probe allows for a pH map extraction. Long relaxation times of pTR allow for pH mapping at EPR irradiation power as low as 1.25 W during 130 s acquisition time with spatial resolution of about 1 mm. This is particularly important for in vivo applications enabling one to avoid sample overheating by reducing RF power deposition. PMID:25530673

  7. [Study of the enzymatic hydrolysis of a phosphonic ester using microcalorimetry].

    PubMed

    Labadie, M; Debord, J; Breton, J C

    1979-01-01

    A "Batch" microcalorimeter is used at 30 degrees C for the study of the hydrolysis of 4-nitro-phenylphenylphosphonate with a calf-intestinal phosphonate esterase, in a tris buffer, pH 8. The yield of enzymatic hydrolysis is estimated by spectrophotometric determination of the p--nitrophenol evolved; we have then calculated the apparent molar enthalph of the reaction. (delta Happ = -72,2 kj. mol-1). Phenylphosphonic acid, the second reaction product, is not transphosphonylated on tris. The second acidity of phenylphosphonic acid was studied at 30 degrees C by sodium hydroxide electrotitration (pKa2 = 7,13) and by "Flow" microcalorimetry (delta Hionization = 19,8 kj.mol-1). In the same manner at 30 degrees C, we measured the heat of ionization of p-nitrophenol (delta Hionization = 26,75 kj.mol-1). These findings allow a calculation for the actual heat of hydrolysis of 4-nitro-phenyl-phenylphosphonate (delta Hrho = -29,7 kj.mol-1).

  8. Adsorption of phosphonate antiscalant from reverse osmosis membrane concentrate onto granular ferric hydroxide.

    PubMed

    Boels, Luciaan; Keesman, Karel J; Witkamp, Geert-Jan

    2012-09-04

    Adsorptive removal of antiscalants offers a promising way to improve current reverse osmosis (RO) concentrate treatment processes and enables the reuse of the antiscalant in the RO desalination process. This work investigates the adsorption and desorption of the phosphonate antiscalant nitrilotris(methylenephosphonic acid) (NTMP) from RO membrane concentrate onto granular ferric hydroxide (GFH), a material that consists predominantly of akaganéite. The kinetics of the adsorption of NTMP onto GFH was predicted fairly well with two models that consider either combined film-pore or combined film-surface diffusion as the main mechanism for mass transport. It is also demonstrated that NTMP is preferentially adsorbed over sulfate by GFH at pH 7.85. The presence of calcium causes a transformation in the equilibrium adsorption isotherm from a Langmuir type to a Freundlich type with much higher adsorption capacities. Furthermore, calcium also increases the rate of adsorption substantially. GFH is reusable after regeneration with sodium hydroxide solution, indicating that NTMP can be potentially recovered from the RO concentrate. This work shows that GFH is a promising adsorbent for the removal and recovery of NTMP antiscalant from RO membrane concentrates.

  9. Rapid Synthesis and Antiviral Activity of (Quinazolin-4-Ylamino)Methyl-Phosphonates Through Microwave Irradiation

    PubMed Central

    Luo, Hui; Hu, Deyu; Wu, Jian; He, Ming; Jin, Linhong; Yang, Song; Song, Baoan

    2012-01-01

    This study describes the simple synthesis of new (quinazolin-4-ylamino) methylphosphonates via microwave irradiation. Substituted-2-aminobenzonitrile reacted with 1,1-dimethoxy-N,N-dimethylmethanamine at a reflux condition to obtain N′-(substituted-2-cyanophenyl)-N,N-dimethylformamidine (1). The subsequent reaction of this intermediate product with α-aminophosphonate (2) in a solution containing glacial acetic acid in 2-propanol through microwave irradiation resulted in the formation of (quinazolin-4-ylamino)methyl-phosphonate derivatives 3a to 3x, which were unequivocally characterized by the spectral data and elemental analysis. The influence of the reaction conditions on the yield of 3a was investigated to optimize the synthetic conditions. The relative optimal conditions for the synthesis of 3a include a 1:1 molar ratio of N′-(2-cyanophenyl)-N,N-dimethylformamidine to diethyl amino(phenyl)methylphosphonate and a 4:1 volume ratio of isopropanol to HOAc in the solvent mixture, at a reaction temperature of 150 °C, with a microwave power of 100 W and a corresponding pressure of 150 psi for 20 min in the microwave synthesizer. The yield of 3a was approximately 79%, whereas those of 3b to 3x were approximately 77% to 86%. Some of the synthesized compounds displayed weak to good anti-Tobacco mosaic virus (TMV) activity. PMID:22837660

  10. Diastereoselectivity in the Mukaiyama-Michael Reaction Employing alpha-Acyl beta,gamma-Unsaturated Phosphonates.

    PubMed

    Telan, Leila A.; Poon, Chi-Duen; Evans, Slayton A.

    1996-10-18

    The unique electronic and structural nature of the alpha-acylphosphonate functional group affords both dimeric and chelated complexes of diethyl crotonyl phosphonate (1; DECP) with stannic chloride (SnCl(4)). The dimeric complex, SnCl(4).(DECP)(2) (5) results from the coordination of two DECP molecules, ligated via the phosphoryl oxygens to the tin atom. The chelated complex, SnCl(4).(DECP) (6), is best represented with both phosphoryl and carbonyl oxygens coordinated to the metal center. Both metal ligated and chelated complexes have unique (13)C (31)P, and (119)Sn NMR spectra. In complex 5, the (13)C NMR resonances attributed to the carbonyl carbons were shifted upfield of free DECP. A monocoordinating Lewis acid, BF(3).OEt(2), produced a similar chemical shift trend in both the (13)C and (31)P NMR spectra of the BF(3).DECP complex. Essentially quantitative yields and moderate diastereomeric excesses favoring anti (or trans) diethyl 6-phenyl-4,5-dimethyl-6-(trimethylsilyloxy)-2-dihydropyranphosphonate (3) and diethyl 5-phenyl-3,4-dimethyl-1,5-dioxopentanephosphonate (4) were obtained from both chelated and dimeric SnCl(4).(DECP)(n) (n = 1, 2) when treated with either diastereomeric (Z)- or (E)-1-phenyl-1-(trimethylsilyloxy)-1-propene 2. Diethyl crotonylphosphonate (1), 3, and 4 were fully characterized.

  11. Highly Ordered Mesostructured Vanadium Phosphonate toward Electrode Materials for Lithium-Ion Batteries.

    PubMed

    Mei, Peng; Pramanik, Malay; Lee, Jaewoo; Ide, Yusuke; Alothman, Zeid Abdullah; Kim, Jung Ho; Yamauchi, Yusuke

    2017-03-28

    Highly ordered mesostructured vanadium phosphonates (VP) have been synthesized in the presence of cetyltrimethylammonium bromide (CTAB) as a structure-directing agent. Nitrilotris(methylene)triphosphonic acid (NMPA) and (ammonium/sodium) metavanadate (NH4 VO3 /NaVO3 ) have been used for the construction of pore walls. The CTAB templates are removed from the materials by an extraction process without destroying the parent mesostructure. The formation mechanism for the ordered mesoporous structure and its impact on electrochemical application in lithium ion batteries (LIBs) are explained by considering the structural and electrochemical stability of the framework. The results demonstrate that the counter cations (NH4(+) /Na(+) ) of the metavanadate precursors have a crucial role in stabilizing the mesoporous structure of the mesoporous VP materials. Mesoporous VP materials with highly ordered structure have great applicability as high-performance electrode materials in LIBs due to the advantages of their large contact area with electrolyte and short transport paths for lithium ions. Mesoporous VP electrodes exhibit high reversible specific capacity with superb cycling stability (100 cycles) and excellent retention of capacity (92 %).

  12. Versatile (bio)functionalization of bromo-terminated phosphonate-modified porous aluminum oxide.

    PubMed

    Debrassi, Aline; Roeven, Esther; Thijssen, Selina; Scheres, Luc; de Vos, Willem M; Wennekes, Tom; Zuilhof, Han

    2015-05-26

    Porous aluminum oxide (PAO) is a nanoporous material used for various (bio)technological applications, and tailoring its surface properties via covalent modification is a way to expand and refine its application. Specific and complex chemical modification of the PAO surface requires a stepwise approach in which a secondary reaction on a stable initial modification is necessary to achieve the desired terminal molecular architecture and reactivity. We here show that the straightforward initial modification of the bare PAO surface with bromo-terminated phosphonic acid allows for the subsequent preparation of PAO with a wide scope of terminal reactive groups, making it suitable for (bio)functionalization. Starting from the initial bromo-terminated PAO, we prepared PAO surfaces presenting various terminal functional groups, such as azide, alkyne, alkene, thiol, isothiocyanate, and N-hydroxysuccinimide (NHS). We also show that this wide scope of easily accessible tailored reactive PAO surfaces can be used for subsequent modification with (bio)molecules, including carbohydrate derivatives and fluorescently labeled proteins.

  13. Bacterial carbon-phosphorus lyase: products, rates, and regulation of phosphonic and phosphinic acid metabolism.

    PubMed Central

    Wackett, L P; Shames, S L; Venditti, C P; Walsh, C T

    1987-01-01

    Carbon-phosphorus bond cleavage activity, found in bacteria that utilize alkyl- and phenylphosphonic acids, has not yet been obtained in a cell-free system. Given this constraint, a systematic examination of in vivo C-P lyase activity has been conducted to develop insight into the C-P cleavage reaction. Six bacterial strains were obtained by enrichment culture, identified, and characterized with respect to their phosphonic acid substrate specificity. One isolate, Agrobacterium radiobacter, was shown to cleave the carbon-phosphorus bond of a wide range of substrates, including fosfomycin, glyphosate, and dialkyl phosphinic acids. Furthermore, this organism processed vinyl-, propenyl-, and propynylphosphonic acids, a previously uninvestigated group, to ethylene, propene, and propyne, respectively. A determination of product stoichiometries revealed that both C-P bonds of dimethylphosphinic acid are cleaved quantitatively to methane and, furthermore, that the extent of C-P bond cleavage correlated linearly with the specific growth rate for a range of substrates. The broad substrate specificity of Agrobacterium C-P lyase and the comprehensive characterization of the in vivo activity make this an attractive system for further biochemical and mechanistic experiments. In addition, the failure to observe the activity in a group of gram-positive bacteria holds open the possibility that a periplasmic component may be required for in vivo expression of C-P lyase activity. PMID:3804975

  14. New water soluble phosphonate and polycarboxylate complexants for enhanced f element separations

    SciTech Connect

    Nash, K.L.; Rickert, P.G.; Lessmann, E.P.; Mendoza, M.D.; Feil, J.F.; Sullivan, J.C.

    1994-08-01

    While lipophilic extractant molecules and ion exchange polymeric materials are clearly essential to efficient separation of metal ions by solvent extraction or ion exchange, the most difficult separations often could not be accomplished without the use of water soluble complexants. This report focuses on recent developments in design, synthesis and characterization of phosphonic acid and polycarboxylic acid ligands for enhanced f element separations. Emphasis is on the basic solution chemistry and crystal structures of complexes of the f elements with selected amino-derivatives of methanediphosphonic acid and with tetrahydrofuran-2,3,4,5-tetracarboxylic acid. The former series of compounds exhibit high affinity for lanthanides and actinides in acidic solutions. The latter ligand exhibits an unusual (and very useful) ``anti-selectivity`` for uranyl ion in a solvent extraction process, which permits efficient separation of uranyl from more radioactive components of nuclear wastes. Most of the observed effects can be explained through examination of the structure of the ligand, and comparison of the spectroscopic and thermodynamic parameters for complexation of various metal ions.

  15. A COMPARISON OF THE SPECIFICITY OF INHIBITION BY PHOSPHONATE ESTERS OF THE FIRST COMPONENT OF COMPLEMENT AND THE ANTIGEN-INDUCED RELEASE OF HISTAMINE FROM GUINEA PIG LUNG

    PubMed Central

    Becker, Elmer L.; Austen, K. Frank

    1964-01-01

    The ability of a number p-nitrophenylethyl alkyl, phenyl alkyl, chloroalkyl, and aminoalkyl phosphonates to inhibit the activated first component (C'1a) of guinea pig complement, and the antigen-induced release of histamine from sliced, perfused guinea pig lung has been compared. C'1a in its reactivity with these phosphonates is distinctly more similar to trypsin than to any of the other enzymes studied previously. It is suggested that both trypsin and C'1a possess an anionic group in the active center of the respective enzyme, but the distance between the anionic and esteratic site in C'1a might be less than in trypsin. The pattern of inhibition of histamine relase by the alkyl, phenyl alkyl, and chloroalkyl phosphonates is similar to the inhibition of C'1a by these compounds, although distinct differences are apparent. The aminoalkyl phosphonates are distinctly less active inhibitors of histamine release than the corresponding alkyl phosphonates, whereas the reverse is true of the inhibition of C'1a. On the basis of these differences, it is tentatively concluded that the organophosphorus-inhibitable enzymes in the guinea pig systems studied here are similar but not identical. PMID:14212115

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

    PubMed

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

    2009-09-03

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

  17. Histidine Triad Nucleotide-binding Protein 1 (HINT-1) Phosphoramidase Transforms Nucleoside 5′-O-Phosphorothioates to Nucleoside 5′-O-Phosphates*

    PubMed Central

    Ozga, Magdalena; Dolot, Rafal; Janicka, Magdalena; Kaczmarek, Renata; Krakowiak, Agnieszka

    2010-01-01

    Nucleoside 5′-O-phosphorothioates are formed in vivo as primary products of hydrolysis of oligo(nucleoside phosphorothioate)s (PS-oligos) that are applied as antisense therapeutic molecules. The biodistribution of PS-oligos and their pharmacokinetics have been widely reported, but little is known about their subsequent decay inside the organism. We suggest that the enzyme responsible for nucleoside 5′-O-monophosphorothioate ((d)NMPS) metabolism could be histidine triad nucleotide-binding protein 1 (Hint-1), a phosphoramidase belonging to the histidine triad (HIT) superfamily that is present in all forms of life. An additional, but usually ignored, activity of Hint-1 is its ability to catalyze the conversion of adenosine 5′-O-monophosphorothioate (AMPS) to 5′-O-monophosphate (AMP). By mutagenetic and biochemical studies, we defined the active site of Hint-1 and the kinetic parameters of the desulfuration reaction (P-S bond cleavage). Additionally, crystallographic analysis (resolution from 1.08 to 1.37 Å) of three engineered cysteine mutants showed the high similarity of their structures, which were not very different from the structure of WT Hint-1. Moreover, we found that not only AMPS but also other ribonucleoside and 2′-deoxyribonucleoside phosphorothioates are desulfurated by Hint-1 at the following relative rates: GMPS > AMPS > dGMPS ≥ CMPS > UMPS > dAMPS ≫ dCMPS > TMPS, and during the reaction, hydrogen sulfide, which is thought to be the third gaseous mediator, was released. PMID:20940308

  18. Molecularly imprinted polymer of 5-methyluridine for solid-phase extraction of pyrimidine nucleoside cancer markers in urine.

    PubMed

    Jégourel, Damien; Delépée, Raphaël; Breton, Florent; Rolland, Antoine; Vidal, Richard; Agrofoglio, Luigi A

    2008-10-01

    Normal and modified urinary nucleosides represent potential biomarkers for cancer diagnosis. To selectively extract modified nucleosides, we developed a molecularly imprinted polymer (MIP) of 5-methyluridine as selective material for molecularly imprinted solid-phase extraction (MISPE). The MIPs were obtained from vinyl-phenylboronate ester derivative of the template, acrylamide and pentaerythritol triacrylate co-polymer, and were tested in batch and cartridge experiments with aqueous samples. Our results indicated that the imprinted polymer was selective for pyrimidine nucleosides with a K(d) and a B(max) of 46 microM and 18 micromol/g, respectively. Finally, a MISPE of the most common pyrimidine nucleoside cancer markers in urine sample was realized.

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

    PubMed

    Jubeli, Emile; Maginty, Amanda B; Khalique, Nada Abdul; Raju, Liji; Nicholson, David G; Larsen, Helge; Pungente, Michael D; Goldring, William P D

    2017-01-05

    In this communication we describe the construction of four succinic-based cationic lipids, their formulation with plasmid DNA (pDNA), and an evaluation of their in vitro gene delivery into Chinese hamster ovarian (CHO-K1) cells. The cationic lipids employed in this work possess either a dimethylamine or trimethylamine headgroup, and a macrocyclic or an acyclic hydrophobic domain composed of, or derived from two 16-atom, succinic-based acyl chains. The synthesized lipids and a co-lipid of neutral charge, either cholesterol or 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), were formulated in an overall 3:2 cationic-to-neutral lipid molar ratio, then complexed with plasmid DNA (pDNA). The relative transfection performance was evaluated via a comparison between matched versus mismatched formulations defined by the rigidity relationship between the lipids employed. Gel electrophoresis was used to characterize the binding of the lipid formulations with plasmid DNA and the relative degree of plasmid degradation using a DNase I degradation assay. Small angle X-ray diffraction (SAXD) was employed to characterize the packing morphology of the lipid-DNA complexes. In general, the succinic unit embedded within the hydrophobic domain of the cationic lipids was found to improve lipid hydration. The transfection assays revealed a general trend in which mismatched formulations that employed a rigid lipid combined with a non-rigid (or flexible) lipid, outperformed the matched formulations. The results from this work suggest that the design of the cationic lipid structure and the composition of the lipoplex formulation play key roles in governing the transfection performance of nonviral gene delivery agents.

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

    PubMed

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

    2016-07-01

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

  1. Acyclic Identification of Aptamers for Human alpha-Thrombin Using Over-Represented Libraries and Deep Sequencing

    PubMed Central

    Kupakuwana, Gillian V.; Crill, James E.; McPike, Mark P.; Borer, Philip N.

    2011-01-01

    Background Aptamers are oligonucleotides that bind proteins and other targets with high affinity and selectivity. Twenty years ago elements of natural selection were adapted to in vitro selection in order to distinguish aptamers among randomized sequence libraries. The primary bottleneck in traditional aptamer discovery is multiple cycles of in vitro evolution. Methodology/Principal Findings We show that over-representation of sequences in aptamer libraries and deep sequencing enables acyclic identification of aptamers. We demonstrated this by isolating a known family of aptamers for human α-thrombin. Aptamers were found within a library containing an average of 56,000 copies of each possible randomized 15mer segment. The high affinity sequences were counted many times above the background in 2–6 million reads. Clustering analysis of sequences with more than 10 counts distinguished two sequence motifs with candidates at high abundance. Motif I contained the previously observed consensus 15mer, Thb1 (46,000 counts), and related variants with mostly G/T substitutions; secondary analysis showed that affinity for thrombin correlated with abundance (Kd = 12 nM for Thb1). The signal-to-noise ratio for this experiment was roughly 10,000∶1 for Thb1. Motif II was unrelated to Thb1 with the leading candidate (29,000 counts) being a novel aptamer against hexose sugars in the storage and elution buffers for Concanavilin A (Kd = 0.5 µM for α-methyl-mannoside); ConA was used to immobilize α-thrombin. Conclusions/Significance Over-representation together with deep sequencing can dramatically shorten the discovery process, distinguish aptamers having a wide range of affinity for the target, allow an exhaustive search of the sequence space within a simplified library, reduce the quantity of the target required, eliminate cycling artifacts, and should allow multiplexing of sequencing experiments and targets. PMID:21625587

  2. Salvadenosine, a 5′-Deoxy-5′-(methylthio) Nucleoside from the Bahamian Tunicate Didemnum sp.

    PubMed Central

    2015-01-01

    Salvadenosine, (1) a rare 5′-deoxy-5′-(methylthio) nucleoside, was isolated from the deep-water Bahaman tunicate Didemnum sp. The structure was solved by integrated analysis of MS and 1D and 2D NMR data. We revise the structure of the known natural product, hamiguanosinol, which is a constitutional isomer of 1, to 5 by interpretation of the spectroscopic data and comparison with synthesized nucleosides. PMID:25284474

  3. Discovery of non-competitive thrombin inhibitor derived from competitive tryptase inhibitor skeleton: Shift in molecular recognition resulted from skeletal conversion of carboxylate into phosphonate.

    PubMed

    Aoyama, Hiroshi; Ijuin, Ryosuke; Kato, Jun-ya; Urushiyama, Sarasa; Tetsuhashi, Masashi; Hashimoto, Yuichi; Yokomatsu, Tsutomu

    2015-09-01

    A novel series of terminal and internal phosphonate esters based on our previously developed aryl carboxylate-type tryptase selective inhibitor 1 was synthesized. The potency of these synthesized compounds was assessed in vitro with an enzyme inhibition assay using three available serine proteases, that is, tryptase, trypsin, and thrombin. The internal phosphonate derivative 6 showed potent thrombin inhibitory activity with an IC50 value of 1.0 μM, whereas it exhibited no or only weak tryptase and trypsin inhibition at 10 μM. The Lineweaver-Burk plot analysis indicates that the inhibition pattern of thrombin with 6 is non-competitive in spite of the fact that the lead carboxylate compound 1 is competitive inhibitor. Therefore, the skeletal conversion of the carboxylate into a phosphonate alters the mode of molecular recognition of these inhibitors by thrombin.

  4. Transport of pyrimidine nucleosides in cells of Escherichia coli K 12.

    PubMed

    Mygind, B; Munch-Petersen

    1975-11-15

    1. The transport of pyrimidine mucleosides into cells of Escherichis coli has been investigated in mutant strains which cannot metabolize these nucleosides. Such cells transport and concentrate purimidine mucleosides several hindredfold. 2. The transport is inhibited by energy poisons and by sulfhydryl reagents. 3. Pyrimidine mucleosides compete mutually for transport. Adenosine is also a strong competitor while guanosine and inosine are weak competitors. 4. The rate of pyrimidine mucleoside transport is shown to be under control of the cytR and deoR gene products, which are also known to regulate the synthesis of nucleoside-catabolizing enzymes. The transport system is repressed by growth on glucose, as is the synthesis of the enzymes.

  5. Enzymatic transesterification of purine nucleoside having a low solubility in organic medium.

    PubMed

    Fan, Hong; Kitagawa, Masaru; Raku, Takao; Tokiwa, Yutaka

    2004-08-01

    Enzymatic transesterification of guanosine having low solubility against organic solvent was examined. For the transesterification between guanosine and divinyl adipate catalyzed by alkaline protease from Bacillus (Bioprase), DMSO was added to DMF to increase the solublility of the nucleoside, and the conversion rate of guanosine to the vinyl guanosine ester was less than 30%. To overcome the reversible inactivation of enzyme by hydrophilic organic solvents, the reaction was carried out with 10% (v/v) water. The transesterification reaction was effectively catalyzed in DMF/DMSO in the presence of water and the conversion rate increased ca. 70% after 7 d reaction. The result shows that the water effect of Bioprase would be a useful method for the synthesis of low solublility nucleoside esters.

  6. Crystal structures of HIV-1 reverse transcriptase complexes with thiocarbamate non-nucleoside inhibitors.

    PubMed

    Spallarossa, Andrea; Cesarini, Sara; Ranise, Angelo; Ponassi, Marco; Unge, Torsten; Bolognesi, Martino

    2008-01-25

    O-Phthalimidoethyl-N-arylthiocarbamates (TCs) have been recently identified as a new class of potent HIV-1 reverse transcriptase (RT) non-nucleoside inhibitors (NNRTIs), by means of computer-aided drug design techniques [Ranise A. Spallarossa, S. Cesarini, F. Bondavalli, S. Schenone, O. Bruno, G. Menozzi, P. Fossa, L. Mosti, M. La Colla, et al., Structure-based design, parallel synthesis, structure-activity relationship, and molecular modeling studies of thiocarbamates, new potent non-nucleoside HIV-1 reverse transcriptase inhibitor isosteres of phenethylthiazolylthiourea derivatives, J. Med. Chem. 48 (2005) 3858-3873]. To elucidate the atomic details of RT/TC interaction and validate an earlier TC docking model, the structures of three RT/TC complexes were determined at 2.8-3.0A resolution by X-ray crystallography. The conformations adopted by the enzyme-bound TCs were analyzed and compared with those of bioisosterically related NNRTIs.

  7. Determination of nucleotides and nucleosides in milks and pediatric formulas: a review.

    PubMed

    Gill, Brendon D; Indyk, Harvey E

    2007-01-01

    Nucleotides and nucleosides play important roles as structural units in nucleic acids, as coenzymes in biochemical pathways, and as sources of chemical energy. Milk contains a complex mixture of nucleotides, nucleosides, and nucleobases, and because of the reported differences in their relative levels in bovine and human milks, pediatric formulas are increasingly supplemented with nucleotides. Liquid chromatography is the dominant analytical technique used for the quantitation of nucleospecies and is commonly applied using either ion-exchange, reversed-phase, or ion-pair reversed-phase modes. Robust methods that incorporate minimal sample preparation and rapid chromatographic separations have been developed for routine product compliance analysis. This review summarizes the analytical techniques used to date in the analysis of nucleospecies in bovine and human milks and infant formulas.

  8. Investigation of the binding between pepsin and nucleoside analogs by spectroscopy and molecular simulation.

    PubMed

    Li, Zhen; Li, Zhigang; Yang, Lingling; Xie, Yuanzhe; Shi, Jie; Wang, Ruiyong; Chang, Junbiao

    2015-03-01

    In this paper, the interactions of pepsin with CYD (cytidine) or nucleoside analogs, including FNC (2'-deoxy-2'-β-fluoro-4'-azidocytidine) and CMP (cytidine monophosphate), were investigated by fluorescence, UV-visible absorption and synchronous fluorescence spectroscopy under mimic physiological conditions. The results indicated that FNC (CYD/CMP) caused the fluorescence quenching by the formation of complex. The binding constants and thermo-dynamic parameters at three different temperatures were obtained. The hydrophobic and electrostatic interactions were the predominant intermolecular forces to stabilize the complex. The F atom in FNC might weaken the binding of nucleoside analog to pepsin. Results showed that CYD was the strongest quencher and bound to pepsin with higher affinity.

  9. Metabolism, Biochemical Actions, and Chemical Synthesis of Anticancer Nucleosides, Nucleotides, and Base Analogs.

    PubMed

    Shelton, Jadd; Lu, Xiao; Hollenbaugh, Joseph A; Cho, Jong Hyun; Amblard, Franck; Schinazi, Raymond F

    2016-12-14

    Nucleoside, nucleotide, and base analogs have been in the clinic for decades to treat both viral pathogens and neoplasms. More than 20% of patients on anticancer chemotherapy have been treated with one or more of these analogs. This review focuses on the chemical synthesis and biology of anticancer nucleoside, nucleotide, and base analogs that are FDA-approved and in clinical development since 2000. We highlight the cellular biology and clinical biology of analogs, drug resistance mechanisms, and compound specificity towards different cancer types. Furthermore, we explore analog syntheses as well as improved and scale-up syntheses. We conclude with a discussion on what might lie ahead for medicinal chemists, biologists, and physicians as they try to improve analog efficacy through prodrug strategies and drug combinations.

  10. A New Alkylation-Elimination Method for Synthesis of Antiviral Fluoromethylenecyclopropane Analogues of Nucleosides

    PubMed Central

    Zhou, Shaoman; Zemlicka, Jiri

    2005-01-01

    A new method for the synthesis of fluoromethylenecyclopropane nucleosides by alkylation-elimination procedure is described. Fluorination of methylenecyclopropane carboxylate 6 gave fluoroester 7. Treatment of 7 with phenylselenenyl bromide afforded the desired ethyl (E)-2-bromomethyl-1-fluoro-2-phenylselenenylcyclopropane-1-carboxylate 11 in 85% yield. DIBALH reduction of 11 gave 13, which after acetylation to 14 was reacted with 2-amino-6-chloropurine to give the 9-alkylated product 15 in 87% yield. Se-oxydation of 15 with hydrogen peroxide afforded 16, which underwent smooth elimination in a mixture of THF-DMF at 60 °C giving rise to a Z,E mixture of protected nucleosides 17. Deacetylation gave Z-1a and E-1a which were separated on a silica gel column. Both Z-1a and E-1a were converted into the respective guanine analogues Z-1b and E-1b. PMID:16801980

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

    SciTech Connect

    Abramchik, Yu. A. Timofeev, V. I. Zhukhlistova, N. E.; Muravieva, T. I.; Esipov, R. S.; Kuranova, I. P.

    2015-07-15

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

  12. Protein preparation, crystallization and preliminary X-ray analysis of Trypanosoma cruzi nucleoside diphosphate kinase 1.

    PubMed

    Gómez Barroso, J A; Pereira, H; Miranda, M; Pereira, C; Garratt, R C; Aguilar, C F

    2010-07-01

    The flagellated protozoan parasite Trypanosoma cruzi is the aetiological agent of Chagas disease. Nucleoside diphosphate kinases (NDPKs) are enzymes that are involved in energy management and nucleoside balance in the cell. T. cruzi TcNDPK1, a canonical isoform, was overexpressed in Escherichia coli as an N-terminally poly-His-tagged fusion protein and crystallized. Crystals grew after 72 h in 0.2 M MgCl(2), 20% PEG 3350. Data were collected to 3.5 A resolution using synchrotron X-ray radiation at the National Synchrotron Light Laboratory (Campinas, Brazil). The crystals belonged to the trigonal space group P3, with unit-cell parameters a = b = 127.84, c = 275.49 A. Structure determination is under way and will provide relevant information that may lead to the first step in rational drug design for the treatment of Chagas disease.

  13. Three-dimensional structure of E. Coli purine nucleoside phosphorylase at 0.99 Å resolution

    NASA Astrophysics Data System (ADS)

    Timofeev, V. I.; Abramchik, Yu. A.; Zhukhlistova, N. E.; Muravieva, T. I.; Esipov, R. S.; Kuranova, I. P.

    2016-03-01

    Purine nucleoside phosphorylases (PNPs) catalyze the reversible phosphorolysis of nucleosides and are key enzymes involved in nucleotide metabolism. They are essential for normal cell function and can catalyze the transglycosylation. Crystals of E. coli PNP were grown in microgravity by the capillary counterdiffusion method through a gel layer. The three-dimensional structure of the enzyme was determined by the molecular-replacement method at 0.99 Å resolution. The structural features are considered, and the structure of E. coli PNP is compared with the structures of the free enzyme and its complexes with purine base derivatives established earlier. A comparison of the environment of the purine base in the complex of PNP with formycin A and of the pyrimidine base in the complex of uridine phosphorylase with thymidine revealed the main structural features of the base-binding sites. Coordinates of the atomic model determined with high accuracy were deposited in the Protein Data Bank (PDB_ID: 4RJ2).

  14. Glucaminium ionic liquid-functionalized stationary phase for the separation of nucleosides in hydrophilic interaction chromatography.

    PubMed

    Jiang, Qiong; Zhang, Mingliang; Wang, Xusheng; Guo, Yong; Qiu, Hongdeng; Zhang, Shusheng

    2015-10-01

    A glucaminium-based ionic liquid stationary phase was prepared via facile epoxy-amine reaction and subsequent quaternization. Successful immobilization of glucaminium-based ionic liquid onto silica surface was validated by elemental analysis and infrared spectroscopy. The new stationary phase was evaluated for the separation of nucleosides in hydrophilic interaction liquid chromatography (HILIC). Effects of various factors, such as acetonitrile concentration, salt concentration, pH value, as well as column temperature, on the chromatographic behavior toward nucleosides were studied in detail. The results indicated that this new stationary phase can be used for separation of water-soluble polar substances in HILIC mode. The retention of solutes on the stationary phase was influenced by a mixed-mode retention mechanism with a combination of adsorptive and partitioning interactions.

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

    NASA Astrophysics Data System (ADS)

    Abramchik, Yu. A.; Timofeev, V. I.; Zhukhlistova, N. E.; Muravieva, T. I.; Esipov, R. S.; Kuranova, I. P.

    2015-07-01

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

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

    PubMed

    Wei, Xiao-Kun; Ding, Qing-Bao; Zhang, Lu; Guo, Yong-Li; Ou, Lin; Wang, Chang-Lu

    2008-07-01

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

  17. Human concentrative nucleoside transporter 1-mediated uptake of 5-azacytidine enhances DNA demethylation.

    PubMed

    Rius, Maria; Stresemann, Carlo; Keller, Daniela; Brom, Manuela; Schirrmacher, Esther; Keppler, Dietrich; Lyko, Frank

    2009-01-01

    The DNA methyltransferase inhibitors 5-azacytidine (5-azaCyd) and 5-aza-2'-deoxycytidine have found increasing use for the treatment of myeloid leukemias and solid tumors. Both nucleoside analogues must be transported into cells and phosphorylated before they can be incorporated into DNA and inactivate DNA methyltransferases. The members of the human equilibrative and concentrative nucleoside transporter families mediate transport of natural nucleosides and some nucleoside analogues into cells. However, the molecular identity of the transport proteins responsible for mediating the uptake of 5-azanucleosides has remained unknown. To this end, we have generated a stably transfected Madin-Darby canine kidney strain II cell line expressing recombinant hCNT1. An antiserum directed against hCNT1 specifically detected the protein in the apical membrane of hCNT1-expressing Madin-Darby canine kidney cells. Using [14C]5-azaCyd, we show here that hCNT1 mediated the Na+-dependent uptake of this drug with a Km value of 63 micromol/L. Na+-dependent transport of radiolabeled cytidine, uridine, and 5-fluoro-5'-deoxyuridine further showed the functionality of the transporter. hCNT1-expressing cells were significantly more sensitive to 5-azaCyd, and drug-dependent covalent trapping of DNA methyltransferase 1 was substantially more pronounced. Importantly, these results correlated with a significant sensitization of hCNT1-expressing cells toward the demethylating effects of 5-azaCyd and 5-aza-2'-deoxycytidine. In conclusion, our study identifies 5-azaCyd as a novel substrate for hCNT1 and provides direct evidence that hCNT1 is involved in the DNA-demethylating effects of this drug.

  18. Nucleoside modifications in the regulation of gene expression: focus on tRNA.

    PubMed

    Duechler, Markus; Leszczyńska, Grażyna; Sochacka, Elzbieta; Nawrot, Barbara

    2016-08-01

    Both, DNA and RNA nucleoside modifications contribute to the complex multi-level regulation of gene expression. Modified bases in tRNAs modulate protein translation rates in a highly dynamic manner. Synonymous codons, which differ by the third nucleoside in the triplet but code for the same amino acid, may be utilized at different rates according to codon-anticodon affinity. Nucleoside modifications in the tRNA anticodon loop can favor the interaction with selected codons by stabilizing specific base pairs. Similarly, weakening of base pairing can discriminate against binding to near-cognate codons. mRNAs enriched in favored codons are translated in higher rates constituting a fine-tuning mechanism for protein synthesis. This so-called codon bias establishes a basic protein level, but sometimes it is necessary to further adjust the production rate of a particular protein to actual requirements, brought by, e.g., stages in circadian rhythms, cell cycle progression or exposure to stress. Such an adjustment is realized by the dynamic change of tRNA modifications resulting in the preferential translation of mRNAs coding for example for stress proteins to facilitate cell survival. Furthermore, tRNAs contribute in an entirely different way to another, less specific stress response consisting in modification-dependent tRNA cleavage that contributes to the general down-regulation of protein synthesis. In this review, we summarize control functions of nucleoside modifications in gene regulation with a focus on recent findings on protein synthesis control by tRNA base modifications.

  19. L-Enantiomers of Transition State Analogue Inhibitors Bound to Human Purine Nucleoside Phosphorylase

    SciTech Connect

    Rinaldo-Matthis,A.; Murkin, A.; Ramagopal, U.; Clinch, K.; Mee, S.; Evans, G.; Tyler, P.; Furneaux, R.; Almo, S.; Schramm, v.

    2008-01-01

    Human purine nucleoside phosphorylase (PNP) was crystallized with transition-state analogue inhibitors Immucillin-H and DADMe-Immucillin-H synthesized with ribosyl mimics of l-stereochemistry. The inhibitors demonstrate that major driving forces for tight binding of these analogues are the leaving group interaction and the cationic mimicry of the transition state, even though large geometric changes occur with d-Immucillins and l-Immucillins bound to human PNP.

  20. Novel indazole non-nucleoside reverse transcriptase inhibitors using molecular hybridization based on crystallographic overlays.

    PubMed

    Jones, Lyn H; Allan, Gill; Barba, Oscar; Burt, Catherine; Corbau, Romuald; Dupont, Thomas; Knöchel, Thorsten; Irving, Steve; Middleton, Donald S; Mowbray, Charles E; Perros, Manos; Ringrose, Heather; Swain, Nigel A; Webster, Robert; Westby, Mike; Phillips, Chris

    2009-02-26

    A major problem associated with non-nucleoside reverse transcriptase inhibitors (NNRTIs) for the treatment of HIV is their lack of resilience to mutations in the reverse transcriptase (RT) enzyme. Using structural overlays of the known inhibitors efavirenz and capravirine complexed in RT as a starting point, and structure-based drug design techniques, we have created a novel series of indazole NNRTIs that possess excellent metabolic stability and mutant resilience.

  1. An environmentally sensitive fluorescent purine nucleoside that changes emission wavelength upon hybridization.

    PubMed

    Saito, Yoshio; Suzuki, Azusa; Okada, Yuji; Yamasaka, Yuki; Nemoto, Nobukatsu; Saito, Isao

    2013-06-25

    C7-naphthylethynylated 8-aza-7-deaza-2'-deoxyguanosine (na)G was synthesized and its photophysical properties were examined. The fluorescent nucleoside exhibited solvatofluorochromic properties (Δλ(fl)(max) = 67 nm). An ODN probe containing (na)G forms a stable base pair only with C and discriminates structural changes such as mismatches and deletions by a distinct change in its emission wavelength.

  2. Stereoselective synthesis of carbocyclic analogues of the nucleoside Q precursor (PreQ0)

    PubMed Central

    2014-01-01

    Summary A convergent and stereoselective synthesis of chiral cyclopentyl- and cyclohexylamine derivatives of nucleoside Q precursor (PreQ0) has been accomplished. This synthetic route allows for an efficient preparation of 4-substituted analogues with interesting three-dimensional character, including chiral cyclopentane-1,2-diol and -1,2,3-triol derivatives. This unusual substitution pattern provides a useful starting point for the discovery of novel bioactive molecules. PMID:24991286

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

    SciTech Connect

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

    2016-12-15

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

  4. Sol-gel synthesis of tantalum oxide and phosphonic acid-modified carbon nanotubes composite coatings on titanium surfaces.

    PubMed

    Maho, Anthony; Detriche, Simon; Delhalle, Joseph; Mekhalif, Zineb

    2013-07-01

    Carbon nanotubes used as fillers in composite materials are more and more appreciated for the outstanding range of accessible properties and functionalities they generate in numerous domains of nanotechnologies. In the framework of biological and medical sciences, and particularly for orthopedic applications and devices (prostheses, implants, surgical instruments, …), titanium substrates covered by tantalum oxide/carbon nanotube composite coatings have proved to constitute interesting and successful platforms for the conception of solid and biocompatible biomaterials inducing the osseous regeneration processes (hydroxyapatite growth, osteoblasts attachment). This paper describes an original strategy for the conception of resistant and homogeneous tantalum oxide/carbon nanotubes layers on titanium through the introduction of carbon nanotubes functionalized by phosphonic acid moieties (-P(=O)(OH)2). Strong covalent C-P bonds are specifically inserted on their external sidewalls with a ratio of two phosphonic groups per anchoring point. Experimental results highlight the stronger "tantalum capture agent" effect of phosphonic-modified nanotubes during the sol-gel formation process of the deposits compared to nanotubes bearing oxidized functions (-OH, -C=O, -C(=O)OH). Particular attention is also paid to the relative impact of the rate of functionalization and the dispersion degree of the carbon nanotubes in the coatings, as well as their wrapping level by the tantalum oxide matrix material. The resulting effect on the in vitro growth of hydroxyapatite is also evaluated to confirm the primary osseous bioactivity of those materials. Chemical, structural and morphological features of the different composite deposits described herein are assessed by X-ray photoelectron spectroscopy (XPS), scanning (SEM) and transmission (TEM) electronic microscopies, energy dispersive X-rays analysis (EDX) and peeling tests.

  5. Effect of time and deposition method on quality of phosphonic acid modifier self-assembled monolayers on indium zinc oxide

    NASA Astrophysics Data System (ADS)

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

    2016-12-01

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

  6. Quaternary Stereogenic Centers through Enantioselective Heck Arylation of Acyclic Olefins with Aryldiazonium Salts: Application in a Concise Synthesis of (R)-Verapamil.

    PubMed

    Oliveira, Caio C; Pfaltz, Andreas; Correia, Carlos Roque Duarte

    2015-11-16

    We describe herein a highly regio- and enantioselective Pd-catalyzed Heck arylation of unactivated trisubstituted acyclic olefins to provide all-carbon quaternary stereogenic centers. Chiral N,N ligands of the pyrimidine- and pyrazino-oxazoline class were developed for that purpose, providing the desired products in good to high yields with enantiomeric ratios up to >99:1. Both linear and branched substituents on the olefins were well-tolerated. The potential of this new method is demonstrated by the straightforward synthesis of several O-methyl lactols and lactones containing quaternary stereocenters, together with a concise enantioselective total synthesis of the calcium channel blocker verapamil.

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

    NASA Technical Reports Server (NTRS)

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

    1989-01-01

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

  8. Synthesis and anti-cancer activities of new sulfonamides 4-substituted-triazolyl nucleosides.

    PubMed

    Alaoui, Soukaina; Dufies, Maeva; Driowya, Mohsine; Demange, Luc; Bougrin, Khalid; Robert, Guillaume; Auberger, Patrick; Pagès, Gilles; Benhida, Rachid

    2017-03-09

    Nucleoside analogues are among the most known drugs commonly used in antiviral and anticancer chemotherapies. Among them, those featuring a five-membered ring nucleobase are of utmost interest such as the anti-cancer agent AICAR or the anti-viral drug ribavirin. Despite its low activity in vitro in different cell lines, AICAR is under clinical development for several pathologies, thanks to its original mode of action. Indeed, AICAR induced autophagy cell death and is able, following this mechanism, to circumvent resistance to apoptotic drugs including kinase inhibitors currently on the market. To improve the activity of AICAR, we report herein an efficient synthesis of new series of sulfonamide-4-substituted-1,2,3-triazolyl nucleosides using a Cu-catalyzed 1,3-dipolar cycloaddition. All these molecules have been fully characterized and evaluated against two aggressive tumor cell lines, RCC4 and MDA-MB-231. Among them, nucleoside analogue 5i belonging to the ribose series was found to be 19 to 66-fold more active than AICAR. Western blot analyses on RCC4 cells showed that 5i displayed an interesting mode of action by inducing both apoptosis and autophagy cell death, making therefore this class of molecules highly promising for further hit-to-lead optimization.

  9. 5-(Dimethoxymethyl)-2′-Deoxyuridine: A Novel Gem Diether Nucleoside with Anti-Orthopoxvirus Activity

    PubMed Central

    Fan, Xuesen; Zhang, Xinying; Zhou, Longhu; Keith, Kathy A.; Kern, Earl R.; Torrence, Paul F.

    2014-01-01

    To provide potential new leads for the treatment of orthopoxvirus infections, the 5-position of the pyrimidine nucleosides have been modified with a gem diether moiety to yield the following new nucleosides: 5-(dimethoxymethyl)-2′-deoxyuridine (2b), 5-(diethoxymethyl)-2′-deoxyuridine (3b), 5-formyl-2′-deoxyuridine ethylene acetal (4b), and 5-formyl-2′-deoxyuridine propylene acetal (5b). These were evaluated in human foreskin fibroblast cells challenged with the vaccinia virus or cowpox virus. Of the four gem diether nucleosides, only the dimethyl gem diether congener showed significant antiviral activity against both viruses. This antiviral activity did not appear to be related to the decomposition to the 5-formyl-2′-deoxyuridine, which was itself devoid of anti-orthopoxvirus activity in these assays. Moreover, at the pH of the in vitro assays, 2b was very stable with a decomposition (to aldehyde) half-life of >15 d. The anti-orthopoxvirus activity of pyrimidine may be favored by the introduction of hydrophilic moieties to the 5-position side chain. PMID:16722657

  10. Zika virus protection by a single low-dose nucleoside-modified mRNA vaccination.

    PubMed

    Pardi, Norbert; Hogan, Michael J; Pelc, Rebecca S; Muramatsu, Hiromi; Andersen, Hanne; DeMaso, Christina R; Dowd, Kimberly A; Sutherland, Laura L; Scearce, Richard M; Parks, Robert; Wagner, Wendeline; Granados, Alex; Greenhouse, Jack; Walker, Michelle; Willis, Elinor; Yu, Jae-Sung; McGee, Charles E; Sempowski, Gregory D; Mui, Barbara L; Tam, Ying K; Huang, Yan-Jang; Vanlandingham, Dana; Holmes, Veronica M; Balachandran, Harikrishnan; Sahu, Sujata; Lifton, Michelle; Higgs, Stephen; Hensley, Scott E; Madden, Thomas D; Hope, Michael J; Karikó, Katalin; Santra, Sampa; Graham, Barney S; Lewis, Mark G; Pierson, Theodore C; Haynes, Barton F; Weissman, Drew

    2017-03-09

    Zika virus (ZIKV) has recently emerged as a pandemic associated with severe neuropathology in newborns and adults. There are no ZIKV-specific treatments or preventatives. Therefore, the development of a safe and effective vaccine is a high priority. Messenger RNA (mRNA) has emerged as a versatile and highly effective platform to deliver vaccine antigens and therapeutic proteins. Here we demonstrate that a single low-dose intradermal immunization with lipid-nanoparticle-encapsulated nucleoside-modified mRNA (mRNA-LNP) encoding the pre-membrane and envelope glycoproteins of a strain from the ZIKV outbreak in 2013 elicited potent and durable neutralizing antibody responses in mice and non-human primates. Immunization with 30 μg of nucleoside-modified ZIKV mRNA-LNP protected mice against ZIKV challenges at 2 weeks or 5 months after vaccination, and a single dose of 50 μg was sufficient to protect non-human primates against a challenge at 5 weeks after vaccination. These data demonstrate that nucleoside-modified mRNA-LNP elicits rapid and durable protective immunity and therefore represents a new and promising vaccine candidate for the global fight against ZIKV.

  11. Thermal unfolding of nucleoside hydrolases from the hyperthermophilic archaeon Sulfolobus solfataricus: role of disulfide bonds.

    PubMed

    Porcelli, Marina; De Leo, Ester; Del Vecchio, Pompea; Fuccio, Francesca; Cacciapuoti, Giovanna

    2012-03-01

    Nucleoside hydrolases are metalloproteins that hydrolyze the N-glycosidic bond of β-ribonucleosides, forming the free purine/pyrimidine base and ribose. We report the stability of the two hyperthermophilic enzymes Sulfolobus solfataricus pyrimidine-specific nucleoside hydrolase (SsCU-NH) and Sulfolobus solfataricus purine-specific inosineadenosine- guanosine nucleoside hydrolase (SsIAG-NH) against the denaturing action of temperature and guanidine hydrochloride by means of circular dichroism and fluorescence spectroscopy. The guanidine hydrochloride-induced unfolding is reversible for both enzymes as demonstrated by the analysis of the refolding process by activity assays and fluorescence measurements. The evidence that the denaturation of SsIAG-NH carried out in the presence of reducing agents proved to be reversible indicates that the presence of disulfide bonds interferes with the refolding process of this enzyme. Both enzymes are highly thermostable and no thermal unfolding transition can be obtained up to 108°C. SsIAG-NH is thermally denatured under reducing conditions (T(m)=93°C) demonstrating the contribution of disulfide bridges to enzyme thermostability.

  12. Single tryptophan of disordered loop from Plasmodium falciparum purine nucleoside phosphorylase: involvement in catalysis and microenvironment.

    PubMed

    Suthar, Manish Kumar; Verma, Anita; Doharey, Pawan Kumar; Singh, Shiv Vardan; Saxena, Jitendra Kumar

    2013-06-01

    Among various tropical diseases, malaria is a major life-threatening disease caused by Plasmodium parasite. Plasmodium falciparum is responsible for the deadliest form of malaria, so-called cerebral malaria. Purine nucleoside phosphorylase from P. falciparum is a homohexamer containing single tryptophan residue per subunit that accepts inosine and guanosine but not adenosine for its activity. This enzyme has been exploited as drug target against malaria disease. It is important to draw together significant knowledge about inherent properties of this enzyme which will be helpful in better understanding of this drug target. The enzyme shows disorder to order transition during catalysis. The single tryptophan residue residing in conserved region of transition loop is present in purine nucleoside phosphorylases throughout the Plasmodium genus. This active site loop motif is conserved among nucleoside phosphorylases from apicomplexan parasites. Modification of tryptophan residue by N-bromosuccinamide resulted in complete loss of activity showing its importance in catalysis. Inosine was not able to protect enzyme against N-bromosuccinamide modification. Extrinsic fluorescence studies revealed that tryptophan might not be involved in substrate binding. The tryptophan residue localised in electronegative environment showed collisional and static quenching in the presence of quenchers of different polarities.

  13. Pseudobond parameters for QM/MM studies involving nucleosides, nucleotides, and their analogs

    SciTech Connect

    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. How- ever, 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 me- chanically 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 nu- cleotide 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 prop- erties, 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 nu- cleoside 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. 2013 American Institute of Physics. [http://dx.doi.org/10.1063/1.4772182

  14. High-throughput five minute microwave accelerated glycosylation approach to the synthesis of nucleoside libraries.

    PubMed

    Bookser, Brett C; Raffaele, Nicholas B

    2007-01-05

    The Vorbrüggen glycosylation reaction was adapted into a one-step 5 min/130 degrees C microwave assisted reaction. Triethanolamine in acetontrile containing 2% water was determined to be optimal for the neutralization of trimethylsilyl triflate allowing for direct MPLC purification of the reaction mixture. When coupled with a NH3/methanol deprotection reaction, a high-throughput method of nucleoside library synthesis was enabled. The method was demonstrated by examining the ribosylation of 48 nitrogen containing heteroaromatic bases that included 25 purines, four pyrazolopyrimidines, two 8-azapurines, one 2-azapurine, two imidazopyridines, two benzimidazoles, three imidazoles, three 1,2,4-triazoles, two pyrimidines, two 3-deazapyrimidines, one quinazolinedione, and one alloxazine. Of these, 32 yielded single regioisomer products, and six resulted in separable mixtures. Seven examples provided inseparable regioisomer mixtures of -two to three compounds (16 nucleosides), and three examples failed to yield isolable products. For the 45 single isomers isolated, the average two-step overall yield +/- SD was 26 +/- 16%, and the average purity +/- SD was 95 +/- 6%. A total of 58 different nucleosides were prepared of which 15 had not previously been accessed directly from glycosylation/deprotection of a readily available base.

  15. Proton Conduction in a Phosphonate-Based Metal-Organic Framework Mediated by Intrinsic "Free Diffusion inside a Sphere".

    PubMed

    Pili, Simona; Argent, Stephen P; Morris, Christopher G; Rought, Peter; García-Sakai, Victoria; Silverwood, Ian P; Easun, Timothy L; Li, Ming; Warren, Mark R; Murray, Claire A; Tang, Chiu C; Yang, Sihai; Schröder, Martin

    2016-05-25

    Understanding the molecular mechanism of proton conduction is crucial for the design of new materials with improved conductivity. Quasi-elastic neutron scattering (QENS) has been used to probe the mechanism of proton diffusion within a new phosphonate-based metal-organic framework (MOF) material, MFM-500(Ni). QENS suggests that the proton conductivity (4.5 × 10(-4) S/cm at 98% relative humidity and 25 °C) of MFM-500(Ni) is mediated by intrinsic "free diffusion inside a sphere", representing the first example of such a mechanism observed in MOFs.

  16. Construction of Uranyl Organic Hybrids by Phosphonate and in Situ Generated Carboxyphosphonate Ligands.

    PubMed

    Liu, Chao; Yang, Weiting; Qu, Ning; Li, Lei-Jiao; Pan, Qing-Jiang; Sun, Zhong-Ming

    2017-02-06

    The hydrothermal reaction of uranyl ions with (5-methyl-1,3-phenylene)diphosphonic acid (H4MPDP) in the presence of additives such as nitric acid, N-bearing species, and heterometal ions yielded five new uranyl organic hybrids: (H3O)[(UO2)5(H2O)4(H3DPB)2(H2DPB)(HDPB)]·2H2O (1), (Hphen)(phen)[(UO2)3(H2DPB)(HDPB)] (2), (H2dipy)[(UO2)3(MPDP)2] (3), Zn(bipy)(UO2)(MPDP) (4), and Co(bipy)(UO2)(MPDP)·H2O (5) (H5DPB = 3,5-diphosphonobenzoic acid; phen = 1,10-phenanthroline; dipy = 4,4'-bipyridine; bipy = 2,2'-bipyridine). Single-crystal X-ray diffraction (XRD) demonstrates that 1 and 2 are 3D frameworks constructed of uranyl centers and carboxyphosphonate DPB ligands; the latter were formed via the in situ oxidation of H4MPDP. In the homometallic uranyl diphosphonate 3, less common UO6 square bipyramids connected by MPDP ligands were incorporated to form the 2D assembly. A further introduction of heterometal ions produced two heterobimetallic uranyl phosphonates 4 and 5. Both of them show layered structures, formed by UO6 square bipyramids linked by MPDP ligands with heterometal-centered polyhedra decorated on the sides of the layers. It is found that the pH and heterometal ions have significant effects on the structures of the complexes. In addition to the syntheses and XRD characterization, the spectroscopic properties of these uranyl complexes were also addressed. To complement the experimental results, density functional theory calculations were carried out on several model complexes that feature a homo- or heterobimetallic molecular skeleton. Geometrical/electronic structures, IR spectra, and electronic absorptions were discussed.

  17. The Fungicide Phosphonate Disrupts the Phosphate-Starvation Response in Brassica nigra Seedlings.

    PubMed Central

    Carswell, C.; Grant, B. R.; Theodorou, M. E.; Harris, J.; Niere, J. O.; Plaxton, W. C.

    1996-01-01

    The development of Brassica nigra seedlings over 20 d of growth was disrupted by the fungicide phosphonate (Phi) in a manner inversely correlated with nutritional inorganic phosphate (Pi) levels. The growth of Pi-sufficient (1.25 mM Pi) seedlings was suppressed when 10, but not 5, mM Phi was added to the nutrient medium. In contrast, the fresh weights and root:shoot ratios of Pi-limited (0.15 mM) seedlings were significantly reduced at 1.5 mM Phi, and they progressively declined to about 40% of control values as medium Phi concentration was increased to 10 mM. Intracellular Pi levels generally decreased in Phi-treated seedlings, and Phi accumulated in leaves and roots to levels up to 6- and 16-fold that of Pi in Pi-sufficient and Pi-limited plants, respectively. Extractable activities of the Pi-starvation-inducible enzymes phosphoenolpyruvate phosphatase and inorganic pyrophosphate-dependent phosphofructokinase were unaltered in Pi-sufficient seedlings grown on 5 or 10 mM Phi. However, when Pi-limited seedlings were grown on 1.5 to 10 mM Phi (a) the induction of phosphoenolpyruvate phosphatase and inorganic pyrophosphate-dependent phosphofructokinase activities by Pi limitation was reduced by 40 to 90%, whereas (b) soluble protein concentrations and the activities of the ATP-dependent phosphofructokinase and pyruvate kinase were unaffacted. It is concluded that Phi specifically interrupts processes involved in regulation of the Pi-starvation response in B. nigra. PMID:12226174

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

    PubMed

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

    2015-03-01

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

  19. A phase I study of samarium-153 ethylenediaminetetramethylene phosphonate therapy for disseminated skeletal metastases

    SciTech Connect

    Turner, J.H.; Claringbold, P.G.; Hetherington, E.L.; Sorby, P.; Martindale, A.A. )

    1989-12-01

    Thirty-five patients with disseminated skeletal metastases from a variety of tumor types underwent clinical trial of samarium-153 ethylenediaminetetramethylene phosphonate (153Sm-EDTMP) on a day-patient basis. Individual beta radiation dosimetry was based on pharmacokinetic studies of a 20 mCi tracer dose of 153Sm-EDTMP. The retained skeletal activity varied unpredictably from 40% to 95% of the administered dose, but in all patients greater than 98% of the nonosseous activity was cleared in the urine within 6 hours. Prospective calculation of radiation dosimetry in each patient permitted an accurate dosage schedule based upon total red marrow exposure, starting at 100 cGy and escalating to 280 cGy to define the dose-limiting myelotoxicity. Pain was relieved in 22 of 34 evaluable patients (65%) for periods ranging from 4 to 35 weeks, following a single administration of 153Sm-EDTMP. Recurrence of pain responded to retreatment with 153Sm-EDTMP in five of nine patients. The dose-limiting toxicity was myelosuppression manifested particularly by delayed thrombocytopenia. Platelet counts less than 100 x 10(9)/L occurred in 42% of courses when bone marrow radiation absorbed dose exceeded 200 cGy. Myelosuppression was transient and platelet counts had recovered to pretreatment levels within 10 weeks of treatment. 153Sm-EDTMP is effective for the amelioration of pain due to disseminated skeletal metastases particularly with carcinoma of breast or prostate where 83% of patients experienced pain relief. In 15 of the 34 evaluable patients there was evidence of stabilization or regression of skeletal metastases on radiographs and follow-up technetium-99m methylene diphosphonate (99mTc-MDP) bone scans.

  20. An ancient prevertebrate Na+-nucleoside cotransporter (hfCNT) from the Pacific hagfish (Eptatretus stouti).

    PubMed

    Yao, Sylvia Y; Ng, Amy M; Loewen, Shaun K; Cass, Carol E; Baldwin, Stephen A; Young, James D

    2002-07-01

    The human concentrative (Na+-linked) plasma membrane transport proteins hCNT1, hCNT2, and hCNT3 are pyrimidine nucleoside-selective (system cit), purine nucleoside-selective (system cif), or broadly selective for both pyrimidine and purine nucleosides (system cib), respectively. All have orthologs in other mammalian species and belong to a gene family (CNT) that has members in insects, nematodes, pathogenic yeast, and bacteria. Here, we report the cDNA cloning and functional characterization of a CNT family member from an ancient marine prevertebrate, the Pacific hagfish (Eptatretus stouti). This Na+-nucleoside symporter, designated hfCNT, is the first transport protein to be characterized in detail in hagfish and is a 683-amino acid residue protein with 13 predicted transmembrane helical segments (TMs). hfCNT was 52, 50, and 57% identical in sequence to hCNT1, hCNT2, and hCNT3, respectively. Similarity to hCNT3 was particularly marked in the TM 4-13 region. When produced in Xenopus oocytes, hfCNT exhibited the transport properties of system cib, with uridine, thymidine, and inosine apparent K(m) values of 10-45 microM. The antiviral nucleoside drugs 3'-azido-3'-deoxythymidine, 2',3'-dideoxycytidine, and 2',3'-dideoxyinosine were also transported. Simultaneous measurement of uridine-evoked currents and radiolabeled uridine uptake under voltage-clamp conditions gave a Na+-to-uridine coupling ratio of 2:1 (cf. 2:1 for hCNT3 and 1:1 for hCNT1/2). The apparent K50 value for Na+ activation was >100 mM. A 50:50 chimera between hfCNT and hCNT1 (TMs 7-13 of hfCNT replaced by those of hCNT1) exhibited hCNT1-like cation interactions, establishing that the structural determinants of cation stoichiometry and binding affinity were located within the carboxy-terminal half of the protein. The high degree of sequence similarity between hfCNT and hCNT3 may indicate functional constraints on the primary structure of the transporter and suggests that cib-type CNTs fulfill important