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  • 1
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    Seventy-five genetic loci influencing the human red blood cell (2012)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2012-12-12
    Description: Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P 〈 10(-8), which together explain 4-9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3623669/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3623669/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉van der Harst, Pim -- Zhang, Weihua -- Mateo Leach, Irene -- Rendon, Augusto -- Verweij, Niek -- Sehmi, Joban -- Paul, Dirk S -- Elling, Ulrich -- Allayee, Hooman -- Li, Xinzhong -- Radhakrishnan, Aparna -- Tan, Sian-Tsung -- Voss, Katrin -- Weichenberger, Christian X -- Albers, Cornelis A -- Al-Hussani, Abtehale -- Asselbergs, Folkert W -- Ciullo, Marina -- Danjou, Fabrice -- Dina, Christian -- Esko, Tonu -- Evans, David M -- Franke, Lude -- Gogele, Martin -- Hartiala, Jaana -- Hersch, Micha -- Holm, Hilma -- Hottenga, Jouke-Jan -- Kanoni, Stavroula -- Kleber, Marcus E -- Lagou, Vasiliki -- Langenberg, Claudia -- Lopez, Lorna M -- Lyytikainen, Leo-Pekka -- Melander, Olle -- Murgia, Federico -- Nolte, Ilja M -- O'Reilly, Paul F -- Padmanabhan, Sandosh -- Parsa, Afshin -- Pirastu, Nicola -- Porcu, Eleonora -- Portas, Laura -- Prokopenko, Inga -- Ried, Janina S -- Shin, So-Youn -- Tang, Clara S -- Teumer, Alexander -- Traglia, Michela -- Ulivi, Sheila -- Westra, Harm-Jan -- Yang, Jian -- Zhao, Jing Hua -- Anni, Franco -- Abdellaoui, Abdel -- Attwood, Antony -- Balkau, Beverley -- Bandinelli, Stefania -- Bastardot, Francois -- Benyamin, Beben -- Boehm, Bernhard O -- Cookson, William O -- Das, Debashish -- de Bakker, Paul I W -- de Boer, Rudolf A -- de Geus, Eco J C -- de Moor, Marleen H -- Dimitriou, Maria -- Domingues, Francisco S -- Doring, Angela -- Engstrom, Gunnar -- Eyjolfsson, Gudmundur Ingi -- Ferrucci, Luigi -- Fischer, Krista -- Galanello, Renzo -- Garner, Stephen F -- Genser, Bernd -- Gibson, Quince D -- Girotto, Giorgia -- Gudbjartsson, Daniel Fannar -- Harris, Sarah E -- Hartikainen, Anna-Liisa -- Hastie, Claire E -- Hedblad, Bo -- Illig, Thomas -- Jolley, Jennifer -- Kahonen, Mika -- Kema, Ido P -- Kemp, John P -- Liang, Liming -- Lloyd-Jones, Heather -- Loos, Ruth J F -- Meacham, Stuart -- Medland, Sarah E -- Meisinger, Christa -- Memari, Yasin -- Mihailov, Evelin -- Miller, Kathy -- Moffatt, Miriam F -- Nauck, Matthias -- Novatchkova, Maria -- Nutile, Teresa -- Olafsson, Isleifur -- Onundarson, Pall T -- Parracciani, Debora -- Penninx, Brenda W -- Perseu, Lucia -- Piga, Antonio -- Pistis, Giorgio -- Pouta, Anneli -- Puc, Ursula -- Raitakari, Olli -- Ring, Susan M -- Robino, Antonietta -- Ruggiero, Daniela -- Ruokonen, Aimo -- Saint-Pierre, Aude -- Sala, Cinzia -- Salumets, Andres -- Sambrook, Jennifer -- Schepers, Hein -- Schmidt, Carsten Oliver -- Sillje, Herman H W -- Sladek, Rob -- Smit, Johannes H -- Starr, John M -- Stephens, Jonathan -- Sulem, Patrick -- Tanaka, Toshiko -- Thorsteinsdottir, Unnur -- Tragante, Vinicius -- van Gilst, Wiek H -- van Pelt, L Joost -- van Veldhuisen, Dirk J -- Volker, Uwe -- Whitfield, John B -- Willemsen, Gonneke -- Winkelmann, Bernhard R -- Wirnsberger, Gerald -- Algra, Ale -- Cucca, Francesco -- d'Adamo, Adamo Pio -- Danesh, John -- Deary, Ian J -- Dominiczak, Anna F -- Elliott, Paul -- Fortina, Paolo -- Froguel, Philippe -- Gasparini, Paolo -- Greinacher, Andreas -- Hazen, Stanley L -- Jarvelin, Marjo-Riitta -- Khaw, Kay Tee -- Lehtimaki, Terho -- Maerz, Winfried -- Martin, Nicholas G -- Metspalu, Andres -- Mitchell, Braxton D -- Montgomery, Grant W -- Moore, Carmel -- Navis, Gerjan -- Pirastu, Mario -- Pramstaller, Peter P -- Ramirez-Solis, Ramiro -- Schadt, Eric -- Scott, James -- Shuldiner, Alan R -- Smith, George Davey -- Smith, J Gustav -- Snieder, Harold -- Sorice, Rossella -- Spector, Tim D -- Stefansson, Kari -- Stumvoll, Michael -- Tang, W H Wilson -- Toniolo, Daniela -- Tonjes, Anke -- Visscher, Peter M -- Vollenweider, Peter -- Wareham, Nicholas J -- Wolffenbuttel, Bruce H R -- Boomsma, Dorret I -- Beckmann, Jacques S -- Dedoussis, George V -- Deloukas, Panos -- Ferreira, Manuel A -- Sanna, Serena -- Uda, Manuela -- Hicks, Andrew A -- Penninger, Josef Martin -- Gieger, Christian -- Kooner, Jaspal S -- Ouwehand, Willem H -- Soranzo, Nicole -- Chambers, John C -- 092731/Wellcome Trust/United Kingdom -- 097117/Wellcome Trust/United Kingdom -- 14136/Cancer Research UK/United Kingdom -- CZB/4/505/Chief Scientist Office/United Kingdom -- ETM/55/Chief Scientist Office/United Kingdom -- G0600705/Medical Research Council/United Kingdom -- G0700704/Medical Research Council/United Kingdom -- G0801056/Medical Research Council/United Kingdom -- G1000143/Medical Research Council/United Kingdom -- G1002084/Medical Research Council/United Kingdom -- G9815508/Medical Research Council/United Kingdom -- HHSN268201100005C/HL/NHLBI NIH HHS/ -- HHSN268201100006C/HL/NHLBI NIH HHS/ -- HHSN268201100007C/HL/NHLBI NIH HHS/ -- HHSN268201100008C/HL/NHLBI NIH HHS/ -- HHSN268201100009C/HL/NHLBI NIH HHS/ -- HHSN268201100010C/HL/NHLBI NIH HHS/ -- HHSN268201100011C/HL/NHLBI NIH HHS/ -- HHSN268201100012C/HL/NHLBI NIH HHS/ -- HHSN271201100005C/DA/NIDA NIH HHS/ -- K12 RR023250/RR/NCRR NIH HHS/ -- MC_U106179471/Medical Research Council/United Kingdom -- MC_U106188470/Medical Research Council/United Kingdom -- N01AG12109/AG/NIA NIH HHS/ -- P01 HL076491/HL/NHLBI NIH HHS/ -- P01 HL098055/HL/NHLBI NIH HHS/ -- P20 HL113452/HL/NHLBI NIH HHS/ -- P30 DK072488/DK/NIDDK NIH HHS/ -- R01 AG018728/AG/NIA NIH HHS/ -- R01 CA165001/CA/NCI NIH HHS/ -- R01 GM053275/GM/NIGMS NIH HHS/ -- R01 HD042157/HD/NICHD NIH HHS/ -- R01 HL059367/HL/NHLBI NIH HHS/ -- R01 HL086694/HL/NHLBI NIH HHS/ -- R01 HL087641/HL/NHLBI NIH HHS/ -- R01 HL087679/HL/NHLBI NIH HHS/ -- R01 HL088119/HL/NHLBI NIH HHS/ -- R01 HL103866/HL/NHLBI NIH HHS/ -- R01 HL103931/HL/NHLBI NIH HHS/ -- R01 LM010098/LM/NLM NIH HHS/ -- R01 MH081802/MH/NIMH NIH HHS/ -- RG/09/012/28096/British Heart Foundation/United Kingdom -- RL1 MH083268/MH/NIMH NIH HHS/ -- U01 GM074518/GM/NIGMS NIH HHS/ -- U01 HG004402/HG/NHGRI NIH HHS/ -- U01 HL072515/HL/NHLBI NIH HHS/ -- U01 HL084756/HL/NHLBI NIH HHS/ -- U24 MH068457/MH/NIMH NIH HHS/ -- U54 RR020278/RR/NCRR NIH HHS/ -- UL1 RR025005/RR/NCRR NIH HHS/ -- UL1 TR000439/TR/NCATS NIH HHS/ -- England -- Nature. 2012 Dec 20;492(7429):369-75. doi: 10.1038/nature11677. Epub 2012 Dec 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cardiology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The Netherlands. p.van.der.harst@umcg.nl〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23222517" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Cycle/genetics ; Cytokines/metabolism ; Drosophila melanogaster/genetics ; Erythrocytes/cytology/*metabolism ; Female ; Gene Expression Regulation/genetics ; *Genetic Loci ; *Genome-Wide Association Study ; Hematopoiesis/genetics ; Hemoglobins/genetics ; Humans ; Male ; Mice ; Organ Specificity ; *Phenotype ; Polymorphism, Single Nucleotide/genetics ; RNA Interference ; Signal Transduction/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Electronic Resource
    Synthesis and pharmacological investigation of stereoisomeric muscarines (1992)
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 4 (1992), S. 230-239 
    Details
    ISSN: 0899-0042
    Keywords: total synthesis ; chiral muscarines ; iodocyclization process ; muscarinic receptor subtypes M1, M2, and M3 ; affinity states ; eudismic ratio ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The synthesis of the eight stereoisomers of muscarine has been efficiently accomplished by utilizing the two enantiomers of lactic esters as starting material. The synthetic strategy is based on a SnCl4-catalyzed addition of allyltrimethylsilane to O-protected lactic aldehydes followed by an iodocyclization process. All the final derivatives possess an enantiomeric excess higher than 98%. The four pairs of enantiomers bound to M1, M2, and M3 muscarinic receptor subtypes in membranes from cerebral cortex, heart, and salivary glands, respectively, and recognized heterogeneous states of the receptors. Of the eight isomers, only natural muscarine (+)-1 recognized three affinity states of the M2 receptor. The compound was also the only one to show selectivity in the binding study, demonstrating 37- to 44-fold higher affinity for the M2 than for the M1 or M3 receptors. In addition, the compounds were tested in functional assays on isolated guinea pig atria (M2 receptors) and ileum (mixed population of M2 and M3 receptors) and their muscarinic potencies were determined. Among the eight isomers, again only (+)-1 enantiomer was found to be very active on both tissues. Its potency was more than two orders of magnitude higher than that of its enantiomer (-)-1 as well as the other six isomers. The eudismic ratios (E.R.) deduced from the two functional tests were 324 and 331. © 1992 Wiley-Liss, Inc.
    Additional Material: 3 Ill.
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    URL: http://dx.doi.org/10.1002/chir.530040406
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    Electronic Resource
    Toxic doses of rac-, (-)-(S)- and (+)-(R)-propranolol in rats and rabbits (1996)
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 8 (1996), S. 411-417 
    Details
    ISSN: 0899-0042
    Keywords: rac-propranolol ; enantiomers ; drug intoxication ; cardiovascular function ; respiratory function ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The contribution of the individual enantiomers ([+]-[R]- and [-]-[S]-propranolol) to rac-propranolol intoxication was studied in anaesthetized, spontaneously breathing (SB) rats and artificially ventilated (AV) rats and rabbits. In the SB rat, propranolol (30 mg.kg-1.h-1 i.v.) decreased heart rate and mean arterial blood pressure and caused hypoventilation, serious hypoxaemia, respiratory acidosis, and death by respiratory arrest. Survival time (ST) in the (+)-(R)-propranolol group (ST 91 ± 5 min) was significantly longer than in the rac-propranolol group (ST 68 ± 6 min). In AV rats and rabbits toxic doses of rac-, (-)-(S)- and (+)-(R)-propranolol, 30 mg.kg-1.h-1 and 15 mg.kg-1.h-1 i.v., respectively, induced comparable effects on haemodynamic variables as in the SB rat. Artificial ventilation lengthened ST by a factor of three to four in rats. In the AV rat, ST's were not significantly different between the rac-, (-)-(S)- and (+)-(R)-propranolol groups. In the rabbit, as in the SB rat, ST in the (+)-(R)-propranolol group was significantly longer than ST's in the rac- and (-)-(S)-propranolol groups. The acute respiratory acidosis in SB rats and the prolonged ST in AV rats suggest that respiratory failure is the primary and cardiovascular failure the secondary cause of death in propranolol intoxication. The potentiation of the toxic effect of the enantiomers observed after dosing the racemate instead of the pure enantiomers could not be explained by a stereoselective difference in plasma propanolol concentration. © 1996 Wiley-Liss, Inc.
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    Electronic Resource
    Amines as leaving groups in nucleophilic aromatic substitution reactions. II.For Part 1, see Reference 1. Hydrolysis of N-(2,4,6-trinitrophenyl)amines (1989)
    Chichester : Wiley-Blackwell
    Journal of Physical Organic Chemistry 2 (1989), S. 507-518 
    Details
    ISSN: 0894-3230
    Keywords: Organic Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Physics
    Notes: The hydrolysis reactions of N-(2,4,6-trinitrophenyl)piperidine (2) and N-(2,4,6-trinitrophenyl)-morpholine (3) were studied. Two kinetic processes well separated in time are observed in both reactions. The fastest process, which is reversible, leads to the formation of a species of λmax 260 and 410 nm and is attributed to the formation of a σ complex of stoichiometry 1 : 2 due to the addition of a second HO- to the σ complex of 1 : 1 stoichiometry. The slowest process leads quantitatively to picrate ion. The equilibrium constants for the formation of the σ complexes of 1:1 and 1:2 stoichiometries and the rate of formation and decomposition of the latter complex were determined. The kinetic data for the slow process lead to the conclusion that the picrate ion is formed from the attack of HO- on the two σ complexes, confirming previous findings. There are some differences in the calculated rates for 2 and 3 which may be an indication that the elimination of the amine is partially rate determining.
    Additional Material: 4 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/poc.610020703
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  • 5
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    Amines as leaving groups in nucleophilic aromatic substitution reactions. III.For Part II, see Ref. 2. Hydrolysis of 1-amino-2,4-dinitrobenzenes (1995)
    Chichester : Wiley-Blackwell
    Journal of Physical Organic Chemistry 8 (1995), S. 113-120 
    Details
    ISSN: 0894-3230
    Keywords: Organic Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Physics
    Notes: The kinetic study of the reaction of 1-pyrrolidino-2,4-dinitrobenzene, 1-piperidino-2,4-dinitrobenzene and 1-morpholino-2,4-dinitrobenzene with NaOH in the presence and absence of the amine leaving group was carried out in aqueous solutions at 25°C, giving 2,4-dinitrophenol as the only product. A mechanism involving the formation of σ complexes by addition of HO- or the amine to the unsubstituted positions of the aromatic ring is proposed. These complexes were found to react faster than the original substrates.
    Additional Material: 3 Ill.
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    URL: http://dx.doi.org/10.1002/poc.610080211
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    Electronic Resource
    Kinetic and equilibrium study of the interaction of N-(1-Ethylpropyl)-3, 4-Dimethyl-2, 6-Dinitroaniline with hydroxide ion (1991)
    Chichester : Wiley-Blackwell
    Journal of Physical Organic Chemistry 4 (1991), S. 277-284 
    Details
    ISSN: 0894-3230
    Keywords: Organic Chemistry ; Physical Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Physics
    Notes: The reversible interaction of N-(1-ethylpropyl)-3, 4-dimethyl-2, 6-dinitroaniline (1) with HO- is characterized by several kinetic processes. The relaxation times of two of them were measured. It is suggested that the faster one is related to the protonation-deprotonation of the 3-methyl group and the value of the protonation rate is 0.19 s-1. The slowest process leads to the dianionic species with maximum absorption at 340 nm where one HO- group adds to the unsubstituted ring position of an anion derived from 1 by deprotonation of either the NH or the 3-methyl group. The rate and equilibrium constants for the formation of this species are reported.
    Additional Material: 4 Ill.
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    URL: http://dx.doi.org/10.1002/poc.610040504
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    Electronic Resource
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    Maravuic acid, a new seco-labdane diterpene from Croton matourensis (1995)
    Weinheim : Wiley-Blackwell
    Liebigs Annalen 1995 (1995), S. 709-710 
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    ISSN: 0947-3440
    Keywords: Diterpenes ; Croton matourensis ; seco-Labdanes ; Supercritical fluid extraction ; Structure elucidation ; 1D and 2D carbon-13 and proton NMR ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: A new seco-labdane diterpene, maravuic acid, has been isolated by supercritical fluid extraction using CO2 from the bark of Croton matourensis Aubl. (Euphorbiaceae). Its structure was elucidated by one and two dimensional NMR methods as (12E)-3,4-seco-labda-4(18),8(20),12,14-tetraen-3-oic acid 2.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/jlac.1995199504103
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    Isolation and Characterisation of (5R, 6S,5′R,8′R)- and (5R,6S,5′R,8′S)-Luteochrome from Brazilian Sweet Potatoes (Ipomoea batatas LAM.) (1986)
    New York, NY : Wiley-Blackwell
    Helvetica Chimica Acta 69 (1986), S. 1554-1558 
    Details
    ISSN: 0018-019X
    Keywords: Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Luteochrome isolated from the tubers of a white-fleshed variety of sweet potato (Ipomoea batatas LAM.) has been shown by HPLC, 1H-NMR and CD spectra to consist of a mixture of (5R,6S,5′R,8′R)- and (5R,6S,5′R,8′S)- 5,6:5′,8′-diepoxy-5,6,5′,8′-tetrahydro-β,β-carotene (1 and 2, resp.). Therefore, its precursor is (5R,6S,5′R,6′S)-5,6:5′,6′-diepoxy-5,6,5′,6′-tetrahydro-β,β-carotene (4). This is the first identification of luteochrome as a naturally occurring carotenoid and, at the same time, gives the first clue to the as yet unknown chirality of the widespread β,β-carotene diepoxide. These facts demonstrate that the enzymic epoxidation of the β-end group occurs from the α-side, irrespective of the presence of OH groups on the ring.
    Additional Material: 4 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/hlca.19860690705
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    Isolation and Absolute Configuration of β,β-Carotene Diepoxide (1988)
    New York, NY : Wiley-Blackwell
    Helvetica Chimica Acta 71 (1988), S. 31-32 
    Details
    ISSN: 0018-019X
    Keywords: Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The 5,6:5′,6′-diepoxy-5,6:5′,6;-tetrahydro-β,β-carotene, isolated from tubers of a white-fleshed variety of sweet potato (Ipomoea batatas LAM.) has been assigned the (5R,6S,5′R,6′S)-chirality on the basis of its HPLC, UV/VIS, and CD data.
    Additional Material: 1 Ill.
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    URL: http://dx.doi.org/10.1002/hlca.19880710104
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    Synthesis of 2′-Deoxy-5-(isothiazol-5-yl)uridine and Its Interaction with the HSV-1 Thymidine Kinase (1996)
    New York, NY : Wiley-Blackwell
    Helvetica Chimica Acta 79 (1996), S. 1462-1474 
    Details
    ISSN: 0018-019X
    Keywords: Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: 2′-Deoxy-5-(isothiazol-5-yl)uridine (12) was synthesized starting from 2′-deoxy-5-iodouridine using a Pd-catalysed cross-coupling reaction with propiolaldehyde diethyl acetal followed by deprotection and ring closure using thiosulfate. 2′-Deoxyuridine 12 has a particular place among the 5-heteroaryl-substituted 2′-deoxyuridines in that it has a high affinity for herpes simplex virus type 1 (HSV-1)-encoded thymidine kinase (TK) without antiviral activity. Biochemical studies revealed that 12 is a substrate for viral TK. We further investigated the interaction of 12 with the HSV-1 thymidine kinase. The conformation of 12 in solution was established by NMR spectroscopy. The most stable conformer 12A has the S-atom of the isothiazole ring placed in the neighbourhood of the C(4)=O group of the pyrimidine moiety. The compound was docked in its most stable conformation in the active site of HSV-1 TK and subjected to energy minimization. This demonstrated that the isothiazole moiety binds in a cavity lined by the side chains of Tyr-132, Arg-163, Ala-167, and Ala-168 and that the C(3) atom of the isothiazole moiety is located in close proximity of the phenolic O-atom of Tyr-132 and the aliphatic part of the Arg-163 side chain.
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    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/hlca.19960790519
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