- Furanose-Pyranose Isomerization of Reduced Pyrimidine and Cyclic Urea Ribosides
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Tetrahydrouridine (THU, 2) and other fully reduced cyclic urea ribofuranosyl nucleosides undergo a rapid, acid-catalyzed isomerization to their more stable ribopyranosyl form.This isomerization is characterized by a change in spectral properties and by a greater than 10-fold decrease in potency for those nucleosides that act as potent inhibitors of cytidine deaminase in their ribofuranose form. 1-(β-D-Ribopyranosyl)hexahydropyrimidin-2-one (7) was synthesized and used in conjuction with its furanose isomer 6 as a model compound for more extensive 1H and 13C NMR, mass spectral, and kinetic studies of this isomerization.The 0.4 δ upfield shift and 4-Hz increase 1H in the J1',2' coupling constant for the pyranose anomeric proton in the 1H NMR spectrum is indicative of a pyranose β-CI conformation in which the aglycon and C-2' and C-4' hydroxyls are equatorial.The mass spectra of trimethylsilylated pyranose nucleosides also show a characteristic large shift in the m/z 204-217 abundance and the appearance of two new rearrangement ions at M - 133 and M - 206.For furanose 6 the rate of isomerization is pH and temperature dependent with pyranose 7 predominating by a factor of 6-9 at equilibrium.At pH 1 and 37 deg C, furanose 6 has an initial half-life of less than 12 min.Accordingly, this isomerization may explain the observed lack of enhanced ara-C levels in studies evaluating the oral administration of an ara-C and THU combination to species with an acidic stomach content.
- Kelley, James A.,Driscoll, John S.,McCormack, John J.,Roth, Jeri S.,Marquez, Victor E.
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- FLUORINATED PYRIMIDINE ANALOGS AND METHODS OF USE THEREOF
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Fluorinated pyrimidine analog compounds, fluorinated pyrimidine analog compounds are including composition, fluorinated pyrimidine analogs method for preparing the compounds of, fluorinated pyrimidine analog compounds administering by inhibiting ladle sacrifice trans DNA, for treating solid tumors, method of treating multiple myeloma is provided. (by machine translation)
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Paragraph 0096; 0100
(2017/01/02)
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- FLUORINATED PYRIMIDINE ANALOGS AND METHODS OF USE THEREOF
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Fluorinated pyrimidine analog compounds, compositions that include the fluorinated pyrimidine analog compounds, methods for making the fluorinated pyrimidine analog compounds, and methods for inhibiting DNA methyltransferase, treating solid tumors, and treating hematologic cancers by administering the fluorinated pyrimidine analog compounds.
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Paragraph 0090
(2014/02/16)
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- FLUORINATED PYRIMIDINE ANALOGS AND METHODS OF USE THEREOF
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Fluorinated pyrimidine analog compounds, compositions that include the fluorinated pyrimidine analog compounds, methods for making the fluorinated pyrimidine analog compounds, and methods for inhibiting DNA methyltransferase, treating solid tumors, and treating hematologic cancers by administering the fluorinated pyrimidine analog compounds.
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Page/Page column 15-16
(2014/09/29)
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- Efficient synthesis of 2′-deoxyzebularine and its α-anomer by the silyl method of N-glycosylation. Crystal structures and conformational study in solution
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2′-Deoxyzebularine and its α-anomer have been efficiently synthesized with relatively high stereoselectivity by a modified procedure of the silyl method of the N-glycosidic bond formation. An SnCl4- catalyzed condensation of silylated pyrimidin
- Ebenryter-Olbinska, Katarzyna,Karolak-Wojciechowska, Janina,Sochacka, Elzbieta
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- Modelling nucleophilic substitution at silicon in solution, using hypervalent silicon compounds based on 2-pyridones
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A novel method for performing structure correlations in solution is described. Examination of how the 13C chemical shifts of the ring carbons of substituted 2-pyridones change on complexation of the oxygen with silicon has enabled the % Si-O bond formation to be determined in solution for a number of pentacoordinate silicon species with 2-pyridones as ligands. The % pentacoordination in these complexes has been determined from the 29Si chemical shift using model compounds for the tetracoordinate and pentacoordinate limiting cases. Correlation of the % Si-O bond formation with % pentacoordination enables the pathway for substitution at silicon to be mapped in solution. The generality of these techniques is examined using a series of related aromatic ligands.
- Bassindale, Alan R.,Borbaruah, Moheswar,Glynn, Simon J.,Parker, David J.,Taylor, Peter G.
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p. 2099 - 2109
(2007/10/03)
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- Chemistry and anti-HIV properties of 2'-fluoro-2',3'- dideoxyarabinofuranosylpyrimidines
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The synthesis, chemistry, biochemistry, and anti-HIV activity of a series of 1-(2,3-dideoxy-2-fluoro-β-D-threo-pentofuranosyl)pyrimidines have been studied in an attempt to find useful anti-AIDS drugs. Synthesis is carried out via a 2,3-dideoxyribose intermediate which facilitates the preparation of analogues by removing the sugar 3'-hydroxyl group prior to, rather than after, condensation with a uracil or cytosine aglycon. The 2'-F-dd-uridine analogues 7a-d (with H, F, Cl, and CH3 substitution in the 5-position) as well as the 4-deoxy compound (12b) are nonprotective to ATH8 or CEM cells infected with HIV-1. In the corresponding cytidine series, the 5-chloro analogue (11) is inactive. However, 2'-fluoro-2',3'- dideoxyarabinosylcytosine, 10a, and its 5-fluoro analogue, 10b, are both active. While neither compound is as potent as ddC or 5-F-ddC (2b), 10b gives complete protection against the cytopathic effects of HIV in both host cell lines. 2'-Fluoro substitution confers increased chemical and enzymatic stability on dideoxynucleosides. Even though dideoxy pyrimidine nucleosides are inherently more stable than the corresponding purine analogues toward acid-catalyzed cleavage of the glycosidic bond, 2'-fluoro substitution (10a) still increases stabilization relative to ddC (2b). No detectable deamination by partially purified cytidine deaminase is observed with the 2'-fluoro compounds 10a, 10b, or 11 under conditions which rapidly deaminate cytidine. A small amount of 2'-F-dd-ara-U (7a) is formed from 10a in monkey plasma after >24 h of exposure. The octanol-water partition coefficients for the dideoxynucleosides in this study indicate their hydrophilic character, with log P values varying from -0.28 to -1.18.
- Siddiqui,Driscoll,Marquez,Roth,Shirasaka,Mitsuya,Barchi Jr.,Kelley
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p. 2195 - 2201
(2007/10/02)
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- Antitumor Properties of 2(1H)-Pyrimidinone Riboside (Zebularine) and Its Fluorinated Analogues
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2(1H)-Pyrimidinone riboside (zebularine, 1b) and its 5-fluoro (6b) and 2'-ara-fluoro (7b) analogues have been synthesized and evaluated in vivo as antitumor agents.Zebularine provides increase in life span (ILS) values of ca. 70percent against intraperito
- Driscoll, John S.,Marquez, Victor E.,Plowman, Jacqueline,Liu, Paul S.,Kelley, James A.,Barchi, Joseph J.
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p. 3280 - 3284
(2007/10/02)
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- 53. Nucleoside und Nucleotide. Teil 22. Synthese eines Tridecanucleosiddodecaphosphats, das die unnatuerliche Base 2(1H)-Pyrimidinon enthaelt
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Nucleosides and Nucleotides.Part 22.Synthesis of a Tridecanucleoside Dodecaphosphate Containing the Unnatural Base 2(1H)-Pyrimidinone.The tridecanucleosid dodecaphosphate d(TpTpMpCpCpTpCpApApApApTpC) incorporating the modified nucleoside 1-(2'-deoxy-β-D-r
- Altermatt, Rolf,Tamm, Christoph
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p. 475 - 483
(2007/10/02)
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- Gas Chromatography/Mass Spectrometry Determination of Urea in Plasma and Application to Urea Metabolism Study
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The study of urea metabolism in human necessitates sensitive methods, so that very low isotopic enrichments of plasma or urinary urea can be measured.A stable derivative of urea, suitable for the measurements of 15N or 13C enrichments of urea using gas chromatography/mass spectrometry, is described.The trimethylsiloxypyrimidine could be used to measure - and urea enrichments as low as 0.5percent with a coefficient of variation below 5percent.Determination of a lower enrichment of urea required the use of 2-trifluoroacetoxypyrimidine, which had a background of0.4 percent at the (M+2) ion.The coefficient of variation in determining the background was 1.6percent; this means a low enrichment, such as 0.1percent, could be determined with confidence.This technique was applied to the study of urea metabolism in humans and dogs.
- Tserng, Kou-Yi,Kalhan, Satish C.
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p. 489 - 491
(2007/10/02)
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