- Modified nucleosides for the treatment of viral infections and abnormal cellular proliferation
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The disclosed invention is a composition for and a method of seating a Flaviviridae (including BVDV and HCV), Orthomyxoviridae (including Influenza A and B) or Paramyxoviridae (including RSV) infection, or conditions related to abnormal cellular proliferation, in a host, including animals, and especially humans, using a nucleoside of general formula (I)-(XXIII) or its pharmaceutically acceptable salt or prodrug. This invention also provides an effective process to quantify the viral load, and in particular BVDV, HCV or West Nile Virus load, in a host, using real-time polymerase chain reaction (“RT-PCR”). Additionally, the invention discloses probe molecules that can fluoresce proportionally to the amount of virus present in a sample.
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- Preparation method of 3'-deoxyuridine
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The invention relates to the field of pharmaceutical synthesis and particularly relates to a preparation method of 3'-deoxyuridine. The method comprises the steps: by adopting a compound 3 as a raw material, firstly protecting amino through acetic anhydride to obtain a compound 4, obtaining a compound 5 under the action of acetyl bromide, reducing through a hypophosphite system to obtain a compound 6; removing deacetylated amino under the action of high-pressure water vapor and an organic solvent to obtain a compound 8 or removing N-acetyl to obtain a compound 7; and finally removing all acetyl to obtain a mixture of 3'-deoxyuridine and 3'-deoxycytidine; separating and purifying to obtain 3'-deoxyuridine crystal and 3'-deoxycytidine crystal separately, or directly removing all acetyl through the compound 6 to obtain the 3'-deoxycytidine. Available natural products are taken as initial raw materials, so that the method is simple in operation and convenient to purify, and industrial large-scale production is extremely easy to implement.
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- Modified nucleosides for the treatment of viral infections and abnormal cellular proliferation
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The disclosed invention is a composition for and a method of treating a Flaviviridae (including BVDV and HCV), Orthomyxoviridae (including Influenza A and B) or Paramyxoviridae (including RSV) infection, or conditions related to abnormal cellular proliferation, in a host, including animals, and especially humans, using a nucleoside of general formula (I)-(XXIII) or its pharmaceutically acceptable salt or prodrug. This invention also provides an effective process to quantify the viral load, and in particular BVDV, HCV or West Nile Virus load, in a host, using real-time polymerase chain reaction (""RT-PCR""). Additionally, the invention discloses probe molecules that can fluoresce proportionally to the amount of virus present in a sample.
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- 2′,3′-Anhydrouridine. A useful synthetic intermediate
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2,2′-Anhydro-1-(β-D-arabinofuranosyl)uracil 1 reacts with sodium hydride in dry DMSO to give 2′,3′-anhydrouridine 2. When the latter compound 2 is heated below its melting point or treated with triethylamine in methanol, it isomerises back to the 2,2′-anhydronucleoside 1. Treatment of compound 1 with sodium ethanethiolate or the sodium salt of benzyl mercaptan in the presence of an excess of the corresponding thiol in DMA gives 2′-S-ethyl-or 2′-S-benzyl-2′-thiouridine (4 or 11) in high yield; however, treatment of the 2,2′-anhydronucleoside 1 first with sodium hydride in DMA and then with a deficiency (with respect to sodium hydride) of ethanethiol or benzyl mercaptan gives the corresponding 3′-S-ethyl or 3′-S-benzyl derivative (3 or 12) in high yield. When the 2,2′-anhydronucleoside 1 is allowed to react with an excess of potassium tert-butoxide in DMSO, the 3′,5′-anhydronucleoside 13 is obtained in good yield. The latter compound 13 undergoes hydrolysis in aqueous trifluoroacetic acid to give 1-(β-D-xylofuranosyl)uracil 14 in high yield. The 3′-S-benzyl derivative 12 is converted by Raney nickel desulfurisation into 3′-deoxyuridine 15 which, in turn, is converted into 3′-deoxycytidine 17 in good yield. X-Ray crystallographic data relating to compounds 11 and 12 are also reported.
- Miah, Anwar,Reese, Colin B.,Song, Quanlai,Sturdy, Zoe,Neidle, Stephen,Simpson, Ian J.,Read, Martin,Rayner, Emma
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p. 3277 - 3283
(2007/10/03)
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- Synthetic nucleosides and nucleotides. XXXV. Synthesis and biological evaluations of 5-fluoropyrimidine nucleosides and nucleotides of 3-deoxy-β- D-ribofuranose and related compounds
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1-O-Acetyl-2,5-di-O-p-chlorobenzoyl-3-deoxy-D-ribofuranose (1), derived from the antibiotic cordycepin was coupled with trimethylsilylated derivatives (2a-c) of N4-propionylcytosine, N4-p-toluoyl-5-fluorocytosine and 5-fluorouracil i
- Saneyoshi,Kohsaka-Ichikawa,Yahata,Kimura,Izuta,Yamaguchi
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p. 2005 - 2009
(2007/10/03)
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- Nucleosides. LVI. Synthesis and chemical modifications of 3'-deoxy- pyrimidine nucleosides
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3'-Deoxyuridine(1) and 3'-deoxycytidine(2) were prepared with improved yields by two different methods applying either the Barton procedure to appropriate 2',5'-di-O-protected pyrimidine nucleosides or by choosing the direct glycosylation of the pyrimidine bases with 1,2-di-O-acetyl-5-O- toluoyl-3-deoxy-D-erythro-pentofuranose via the silylation approach. Suitable protecting groups for the sugar moiety have been found in the trityl, tert- butyldimethylsilyl and the thexyl groups which are inert in the radical deoxygenation process. The newly synthesised compounds were characterized by elemental analyses and UV and 1H-NMR spectra.
- Rhie,Pfleiderer
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p. 1425 - 1452
(2007/10/02)
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- Synthesis of 2'-C-cyano-2'-deoxy- And 2'-C-cyano-2',3'-dideoxy-β-D-arabinofuranosyl Nucleosides
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A series of 2'-C-cyano-2'-deoxy- and 2'-C-cyano-2',3'-dideoxy arabinofuranosyl nucleosides have been prepared by reaction of the corresponding 2'-ulosyl- and 3'-deoxy-2'-ulosyl nucleosides with sodium cyanide followed by 2'-deoxygenation of the cyanohydri
- Velazquez, Sonsoles,Camarasa, Maria-Jose
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p. 1683 - 1694
(2007/10/02)
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- Synthesis and Anticancer Activity of Various 3'-Deoxy Pyrimidine Nucleoside Analogues and Crystal Structure of 1-(3-Deoxy-β-D-threo-pentofuranosyl)cytosine
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Various 3'-deoxy pyrimidine nucleoside analogues have been synthesized for evaluation as potential anticancer and antiviral agents.Among these compounds, 1-(3-deoxy-β-D-threo-pentofuranosyl)cytosine (10, 3'-deoxy-ara-C) and 3'-deoxycytidine (22) had significant anticancer activity against CCRF-CEM, L1210, P388, and S-180 cancer cell lines in vitro, producing ED50 values of 2,10,5,and 34 μM, respectively, for 3'-deoxy-ara-C (10); and 25, 5, 2.5, and 15μM, respectively, for 3'-deoxycytidine (22).Thus, 3'-deoxy-ara-C (10) was 12.5 times more active against CCRF-CEM cells than 3'-deoxycytidine (22).The 2'-O-acetyl, 5'-O-acetyl, and 2',5'-di-O-acetyl derivatives of 3'-derivatives of 3'-deoxy-ara-C (10), compounds 34, 31, and 30, demonstrated anticancer activity in the same range as 3'-deoxy-ara-C (10) against CCRF-CEM, L1210, P388, and S-180 cells.The 5'-O-acetyl derivative (31) had significantly greater activity against CCRF-CEM with an ED50 value of 0.4 but this compound also showed similar activity, as did 3'-deoxy-ara-C against L1210, P388, and S-180 with ED50 values of 3, 3, and 13 μM, respectively. 3'-Deoxy-ara-C was also evaluated in vitro against HSV-2, HCMV, and GPCMV viruses and was found to be not very active with respective IC50 values of 110, 220, and 1000 μM.The single-crystal structure of 3'-deoxy-ara-C (10) was determined by X-ray crystallography.There are two molecules of the nucleoside and one molecule of water in the asymmetric unit.The sugar moieties of two nucleoside molecules adopt different conformations.In molecule A, the ring pucker is C3'-endo with P=18.7 deg and τm= 37.3 deg, while the CH2OH side chain is gauche+.In molecule B, the ring pucker is C2'-endo with P= 156.8 deg and τm = 37.8 deg and the side chain is trans.
- Lin, Tai-Shun,Yang, Jin-Hua,Liu, Mao-Chin,Shen, Zhi-Yi,Cheng, Yung-Chi,et al.
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p. 693 - 701
(2007/10/02)
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