- Chemical Conversion of Thymidine into 5-Methyl-2'-deoxycytidine
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In aqueous ammonia, 5-methyl-4-(1,2,4-triazol-1-yl)-1-(β-D-3,5-di-O-acetyl-2-deoxyribofuranosyl)pyrimidin-2(1H)-one, which can be prepared from thymidine, yields 5-methyl-2'-deoxycytidine.
- Sung, Wing L.
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- Discovery of novel N4-alkylcytidines as promising antimicrobial agents
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The emergence of drug-resistant strains of pathogenic microorganisms necessitates the creation of new drugs. In order to find new compounds that effectively inhibit the growth of pathogenic bacteria and fungi, we synthesized a set of N4-derivat
- Alexandrova, Liudmila A.,Jasko, Maxim V.,Negrya, Sergey D.,Solyev, Pavel N.,Shevchenko, Oleg V.,Solodinin, Andrei P.,Kolonitskaya, Daria P.,Karpenko, Inna L.,Efremenkova, Olga V.,Glukhova, Alla A.,Boykova, Yuliya V.,Efimenko, Tatiana A.,Kost, Natalya V.,Avdanina, Darya A.,Nuraeva, Gulgina K.,Volkov, Ivan A.,Kochetkov, Sergey N.,Zhgun, Alexander A.
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- Synthesis of novel nucleoside 5′-triphosphates and phosphoramidites containing alkyne or amino groups for the postsynthetic functionalization of nucleic acids
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A series of novel nucleoside 5′-triphosphates and phosphoramidites containing alkyne or amino groups for the postsynthetic functionalization of nucleic acids were designed and synthesized. For this purpose, the new 3-aminopropoxypropynyl linker group was used. It contains two alternative functional capabilities: an amino group for the reaction of amino-alkynyl- modified oligonucleotides with corresponding activated esters and an alkyne group for the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. It was shown that a variety of methods of the attachment of the new linker can be used to synthesize a diversity of modified pyrimidine nucleosides. Copyright Taylor and Francis Group, LLC.
- Vasilyeva, Svetlana V.,Budilkin, Boris I.,Konevetz, Dmitrii A.,Silnikov, Vladimir N.
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p. 753 - 767
(2012/07/28)
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- 5-Substituted N4-hydoxy-2'-deoxycytidines and their 5'-monophosphates: Synthesis, conformation, interaction with tumor thymidylate synthase, and in vitro antitumor activity
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Convenient procedures are described for the synthesis of 5-substituted, N4,hydroxy-2'-deoxycytidines 5a,b,d-h via transformation of the respective 5-substituted 3',5'-di-O-acetyl-2'-deoxyuridines 1a-c,e-h. These procedures involved site-specific triazolation or N-methylimidazolation at position C(4), followed by hydroxylamination and deblocking with MeOH-NH3. Nucleosides 5a,b,d-h were selectively converted to the corresponding 5'-monophosphates 6a,b,d-h with the aid of the wheat shoot phosphotransferase system. Conformation of each nucleoside in D2O solution, deduced from 1H NMR spectra and confirmed by molecular mechanics calculations, showed the pentose ring to exist predominantly in the conformation S (C-2'-endo) and the N4-OH group as the cis rotamer. Cell growth inhibition was studied with two L5178Y murine leukemia cell lines, parental and 5-fluoro-2'-deoxyuridine (FdUrd)-resistant, the latter 70-fold less sensitive toward FdUrd than the former. With FdUrd-resistant L5178Y cells, 5-fluoro-N4-hydroxy-2'-deoxycytidine (5e) caused almost 3-fold stronger growth inhibition than FdUrd; 5e was only some 3-fold weaker growth inhibitor of the resistant cells than of the parental cells. Thymidylate synthase inhibition was studied with two forms of the enzyme differing in sensitivities toward 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP), isolated from parental and FdUrd-resistant L1210 cell lines. All N4-hydroxy-dCMP (6a,b,d-h) and dUMP analogues studied were competitive vs dUMP inhibitors of the enzyme. Analogues 6b,d-h and 5-hydroxymethyl-dUMP, similar to N4-hydroxy-dCMP (6a) and FdUMP, were also N5,N10-methylenetetrahydrofolate-dependent, hence mechanism-based, slow-binding inhibitors. 5-Chloro-dUMP, 5-bromo-dUMP, and 5-iodo-dUMP, similar to dTMP, did not cause a time-dependent inactivation of the enzyme. Instead, they behaved as classic inhibitors of tritium release from [5-3H]dUMP. 5-Bromo-dUMP and 5-iodo-dUMP showed substrate activity independent of N5,N10-methylenetetrahydrofolate in the thymidylate synthase-catalyzed dehalogenation reaction. The =N-OH substituent of the pyrimidine C(4) prevented the enzyme-catalyzed release from the C(5) of Br- and I- (the same shown previously for H+). While FdUMP and 6a showed a higher affinity and greater inactivation power with the parental cell than FdUrd-resistant cell enzyme, an opposite relationship could be seen with 5-hydroxymethyl-dUMP.
- Felczak,Miazga,Poznanski,Bretner,Kulikowski,Dzik,Golos,Zielinski,Ciesla,Rode
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p. 4647 - 4656
(2007/10/03)
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- Synthesis and anti-HIV activity of C4-modified pyrimidine nucleosides
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One-pot syntheses provided a series of triazole- and pentafluorophenyloxy-substituted pyrimidine nucleosides. Most of the compounds in the series displayed anti-HIV activities but none as potent as AZT 2. 1-(β-D-Erythro-pentofuranosyl)-4-pentafluorophenyloxy-2(1H)-pyrimidinone 14 was the most potent and the most selective compound in the series with EC50 = 1.6 μM.
- Wallis, Mark P.,Mahmood, Naheed,Fraser, William
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- Synthesis of 5-methyl-2'-O-deoxycytidine analogs to determine monoclonal antibody specificity in the recognition of the 6-(p-bromobenzoylamino) caproyl radical
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Eight new p-bromobenzoyl derivatives of 5-methyl-2'-O-deoxycytidine analogs, substituted at the 4-position, were synthesized. The best conditions for obtaining 5-methyl-4-N-aminoalkyl-2'-O-deoxycytidine from 3',5'-di-O- acetyl-4-(1,2,4-triazol-1-yl)-2'-O-deoxythymidine were studied. The nucleoside analogs were used to identify the fragment of the 6-(p- bromobenzoylamino)caproyl radical that binds to the monoclonal antibody obtained against it and to define an affinity scale of monoclonal antibody against them.
- Rodriguez-Tanty,Higginson-Clarke,Hernandez,Perez,Velez- Castro,Riveron,Macias
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p. 455 - 467
(2007/10/03)
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- Introduction of an immunochemical label in a cytidine analogue
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A new immunochemical label was synthesized and used as an artificial hapten to obtain a monoclonal antibody that specifically recognizes it. The new cytidine analogues, 5-methyl-4-N-{4-[6-(p-bromobenzoylamido)caproylamido]but-1-yl }-2'-de oxycytidine and
- Tanty,Lopez-Canovas,Brauet,Paredes,Clarke,Castro,Rojas,Cabrera
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p. 219 - 228
(2007/10/02)
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- Solid-phase synthesis of oligonucleotides containing 4-alkoxythymidine residues
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Immobilized and fully protected oligodeoxynucleotides containing a 4-(1,2,4-triazolyl)thymidine residue at a predetermined position were prepared according to a well-established phosphite triester methodology using 2-cyanoethyl phosphoramidites of a 4-(1,2,4-triazolyl)-substituted thymidine and standard protected nucleosides.Treatment of the immobilized oligomer with methanol, ethanol or n-propanol in the presence of DBU at 50 deg C gave the corresponding oligonucleotides containing 4-methoxy, 4-ethoxy or 4-n-propoxythymidine residue.
- Roelen, H. C. P. F.,Brugghe, H. F.,Elst, H. van den,Marel, G. A. van der,Boom, J. H. van
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- Synthesis and antiviral properties of (E)-5-(2-bromovinyl)-2'-deoxycytidine-related compounds
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Treatment of 3',5'-di-O-acetyl-(E)-5-(2-bromovinyl)-2'-deoxyuridine (2) with p-chlorophenyl phosphorodichloridate and 1,2,4-triazole gave 1-(3,5-di-O-acetyl-2-deoxy-β-D-erythro-pentofuranosyl)-(E)-5-(2-brom vinyl)-4-(1,2,4-triazol-1-yl)pyrimidin-2(1H)-one (3). Reaction of 3 with ammonia gave (E)-5-(2-bromovinyl)-2'-deoxycytidine (1), the overall yield from 2 being 60%. A similar 4-(1,2,4-triazol-1-yl) derivative (4) was obtained from 3',5'-di-O-acetylthymidine by the use of phosphoryl chloride as the condensing agent. Treatment of thymidine with trimethylsilyl chloride and then with phosphoryl chloride and 1,2,4-triazole gave upon workup 1-(2-deoxy-β-D-erythro-pentofuranosyl)-5-methyl-4(1,2,4-triazol-1-yl pyrimidin-2(1H)-one (5). (E)-5-(2-Bromovinyl)-2'-deoxyuridine (BVDU) when similarly treated gave the corresponding (E)-5-(2-bromovinyl) compound 7. A minor product formed in both cases was a 4-(1,2,4-triazol-1-yl) derivative in which the nucleoside 5'-hydroxyl group had been replaced by chlorine (6 and 8). Whereas compounds 4-6 and 8 did not exhibit a selective antiviral effect, compounds 1-3 and 7 proved almost as active as the reference compound BVDU. In particular, compound 7, the 4-triazolyl derivative of BVDU, would seem worth pursuing for its potential as an inhibitor of herpes simplex virus type 1 and varicella-zoster virus.
- Jones,Sayers,Walker,De Clercq
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p. 268 - 271
(2007/10/02)
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- REACTION BETWEEN NUCLEOSIDE BASE AND THE PHOSPHORYLATING AGENT DERIVED FROM 1-HYDROXYBENZOTRIAZOLE AND 2-CHLOROPHENYL PHOSPHORODICHLORIDATE
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In the presence of 1-methylimidazole, 2-N-acyl guanine (as in 4a), thymine (as in 5a), and uracil (as in 5b) residues react readily with the phosphorylating agent derived from 2-chlorophenyl phosphorodichloridate (1a) and 1-hydroxybenzotriazole.
- Reese, Colin B.,Richards, Keith H.
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p. 2245 - 2248
(2007/10/02)
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