- Rhodium-catalyzed reductive modification of pyrimidine nucleosides, nucleotide phosphates, and sugar nucleotides
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Nucleosides and nucleotides are a group of small molecule effectors and substrates which include sugar nucleotides, purine and pyrimidine-based nucleotide phosphates, and diverse nucleotide antibiotics. We previously reported that hydrogenation of the nucleotide antibiotic tunicamycin leads to products with reduced toxicity on eukaryotic cells. We now report the hydrogenation of diverse sugar nucleosides, nucleotide phosphates, and pyrimidine nucleotides. UDP-sugars and other uridyl and thymidinyl nucleosides are quantitatively reduced to the corresponding 5,6-dihydro-nucleosides. Cytidyl pyrimidines are reduced, but the major products are the corresponding 5,6-dihydrouridyl nucleosides resulting from a deamination of the cytosine ring.
- Price, Neil P.J.,Jackson, Michael A.,Vermillion, Karl E.,Blackburn, Judith A.,Hartman, Trina M.
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- Selective catalytic hydrogenation of the N-acyl and uridyl double bonds in the tunicamycin family of protein N-glycosylation inhibitors
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Tunicamycin is a Streptomyces-derived inhibitor of eukaryotic protein N-glycosylation and bacterial cell wall biosynthesis, and is a potent and general toxin by these biological mechanisms. The antibacterial activity is dependent in part upon a π-π stacking interaction between the tunicamycin uridyl group and a specific Phe residue within MraY, a tunicamycin-binding protein in bacteria. We have previously shown that reducing the tunicamycin uridyl group to 5,6-dihydrouridyl (DHU) significantly lowers its eukaryotic toxicity, potentially by disrupting the π-stacking with the active site Phe. The present report compares the catalytic hydrogenation of tunicamycin and uridine with various precious metal catalysts, and describe optimum conditions for the selective production of N-acyl reduced tunicamycin or for tunicamycins reduced in both the N-acyl and uridyl double bonds. At room temperature, Pd-based catalysts are selective for the N-acyl reduction, whereas Rh-based catalysts favor the double reduction to provide access to fully reduced tunicamycin. The reduced DHU is highly base-sensitive, leading to amide ring opening under mild alkaline conditions.
- Price, Neil P.J.,Jackson, Michael A.,Vermillion, Karl E.,Blackburn, Judith A.,Li, Jiakun,Yu, Biao
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- TUNICAMYCIN RELATED COMPOUNDS WITH ANTI-BACTERIAL ACTIVITY
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Tunicamycin related compounds having an acyl chain double bond reduced and/or having an acyl chain double bond and an uracil ring double bond reduced are described as well as methods of making these tunicamycin related compounds. These tunicamycin related compounds are not toxic to eukaryotic cells and can be used to kill Gram-positive bacteria, alone or in combination with other antibiotics. Use of these tunicamycin related compounds to kill Gram-positive bacteria, treat Gram-positive bacterial diseases, and disinfect objects or surfaces are described. In addition, naturally-occurring streptovirudin compounds are not toxic to eukaryotic cells and can be used to kill Gram-positive bacteria, alone or in combination with other antibiotics.
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Paragraph 0015; 0061
(2018/08/09)
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- Selective fluorescence-based detection of dihydrouridine with boronic acids
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The first fluorescent sensing system for dihydrouridine detection is presented. Dihydrouridine is the single most frequently occurring post-transcriptional modification in tRNA from bacteria and eukaryotes. A series of 10 boronic acid derivatives was prepared and their fluorogenic behaviours towards dihydrouridine and uridine were investigated. Whereas uridine always quenches fluorescence via π-π stacking interactions, several boronic acid sensors have been found to show substantial fluorescence enhancement upon binding with dihydrouridine.
- Luvino, Delphine,Smietana, Michael,Vasseur, Jean-Jacques
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p. 9253 - 9256
(2008/02/10)
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- Facile deprotection of O-Cbz-protected nucleosides by hydrogenolysis: An alternative to O-benzyl ether-protected nucleosides
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(Chemical Equation Presented) Because of side-reactions encountered during hydrogenolysis, benzyl ethers are usually not an effective protecting group for nucleosides. Benzyloxycarbamates provide an alternative to traditional benzyl ethers for protection of nucleoside hydroxyl groups, as they are much more labile to hydrogenolysis. Deprotection conditions using transfer hydrogenolysis are described that avoid the reduction of the pyrimidine nucleobase during deblocking of O-Cbz-protected nucleosides. Additionally, an experiment is described that suggests the nucleobase component of a nucleoside is responsible for the sluggish hydrogenolysis of nucleosides.
- Johnson II, David C.,Widlanski, Theodore S.
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p. 4643 - 4646
(2007/10/03)
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- Nucleosides, XXXVII. - Synthesis and Properties of 2'-O- and 3'-O-(tert-Butyldimethylsilyl)-5'-O-(4-methoxytrityl)- and 2',3'-Bis(O-tert-butyldimethylsilyl)ribonucleosides - Starting Materials for Oligoribonucleotide Syntheses
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The synthesis of aminoacylated 5'-O-(4-methoxytrityl)ribonucleosides of adenosine (1), guanosine (9), cytidine (31), uridine (17), and 5,6-dihydrouridine (23) have been optimized and these compounds (4, 12, 33, 18 and 24) silylated by tert-butyldimethylsilyl chloride.The corresponding 2'- and 3'-mono-O- as well as 2',3'-bis-O-(tert-butyldimethylsilyl) derivatives have been isolated by combination of chromatographical methods and fractional crystallization procedures in preparative scale.The characterization of the newly synthesized compounds was achieved by UV and 13C-NMR spectra.
- Flockerzi, Dieter,Silber, Gunter,Charubala, Ramamurthy,Schlosser, Wilhelm,Varma, Rajendra Singh,et al.
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p. 1568 - 1585
(2007/10/02)
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- Organic compounds and process
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Novel hydrogenated pyrimidine nucleosides and nucleotides are produced by catalytic hydrogenation, particularly in the presence of a rhodium catalyst. The novel compounds are specifically used to inhibit deaminating enzymes, which would inactivate cytosine arabinoside by conversion to uridine arabinoside. Cytosine arabinoside is used for its anti-viral, particularly anti-herpes and anticytotoxic activity in mammals and birds, as well as to destroy phages which interfere with the production of antibiotics. Novel formulations containing cytosine arabinoside and the hydrogenated pyrimidine nucleosides are advantageous to provide prolonged cytosine arabinoside effects.
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