- Design, synthesis, and antiviral activity of 2′-deoxy-2′- fluoro-2′-C-methylcytidine, a potent inhibitor of hepatitis C virus replication
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The pyrimidine nucleoside beta-D-2′-deoxy-2′-fluoro-2′-C- methylcytidine (1) was designed as a hepatitis C virus RNA-dependent RNA polymerase (HCV RdRp) inhibitor. The title compound was obtained by a DAST fluorination of N4-benzoyl-1-(2-methyl-3,5-di-O-benzoyl-β-D- arabinofuranosyl]cytosine (6) to provide N4-benzoyl-1-[2-fluoro-2- methyl-3,5-di-O-benzoyl-β-D-ribofuranosyl]cytosine (7a). The protected 2′-C-methylcytidine (7c) was obtained as a byproduct from the DAST fluorination and allowed for the preparation of two biologically active compounds from a common precursor. Compound 1 and 2′-C-methylcytidine were assayed in a subgenomic HCV replicon assay system and found to be potent and selective inhibitors of HCV replication. Compound 1 shows increased inhibitory activity in the HCV replicon assay compared to 2′-C-methylcytidine and low cellular toxicity.
- Clark, Jeremy L.,Hollecker, Laurent,Mason, J. Christian,Stuyver, Lieven J.,Tharnish, Phillip M.,Lostia, Stefania,McBrayer, Tamara R.,Schinazi, Raymond F.,Watanabe, Kyoichi A.,Otto, Michael J.,Furman, Phillip A.,Stec, Wojciech J.,Patterson, Steven E.,Pankiewicz, Krzysztof W.
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p. 5504 - 5508
(2007/10/03)
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- Synthesis and Anticancer and Antiviral Activities of Various 2'- and 3'-Methylidene-Substituted Nucleoside Analogues and Crystal Structure of 2'-Deoxy-2'-methylidenecytidine Hydrochloride
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Various 2'- and 3'-methylidene-substituted nucleoside analogues have been synthesized and evaluated as potential anticancer and/or antiviral agents.Among these compounds, 2'-deoxy-2'-methylidene-5-fluorocytidine (22) and 2'-deoxy-2'-methylidenecytidine (23) not only demonstrated potent anticancer activity in culture against murine L1210 and P388 leukemias, Sarcoma 180, and human CCRF-CEM lymphoblastic leukemia, producing ED50 values of 1.2 and 0.3 μM, 0.6 and 0.4 μM, 1.5 and 1.5 μM, and 0.05 and 0.03 μM, respectively, but also were active in mice against murine L1210 leukemia.Of all the tested drug dosage levels (25, 50, and 75 mg/kg, respectively) compound 23 had no toxic deaths and compound 22 yielded only one toxic death at the highest dosage level.On the contrary, in the same study, 1-β-D-arabinofuranosylcytosine (ara-C) resulted in 2/5, 5/5, and 5/5 toxic deaths, respectively.Both compounds 22 and 23 have shown better anticancer activity than ara-C, yielding higher T/C * 100 values and some long-term survivors ( > 60 days).In addition, compounds 22 and 23 were found to have, respectively, approximately 130 and 40 times lower binding affinity for cytidine/deoxycytidine deaminase derived from human KB cells compared to ara-C, suggesting that the two 2'-methylidene-substituted analogues may be more resistant to deamination.Cytoplasmic deoxycytidine kinase (dCK) was required for compounds 22 and 23 action.Furthermore, compounds 14, 22, 23, and 24 also have antiherpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) activity in cell culture.In addition, the crystal structure of 2'-deoxy-2'-methylidenecytidine hydrochloride (23*HCl) was determined by X-ray crystallography.
- Lin, Tai-Shun,Luo, Mei-Zhen,Liu, Mao-Chin,Clarke-Katzenburg, Regina H.,Cheng, Yung-Chi,et al.
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p. 2607 - 2615
(2007/10/02)
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- Stereoselective addition of a Wittig reagent to give a single nucleoside oxaphosphetane diastereoisomer. Synthesis of 2'(and 3')-deoxy-2'(and 3')-methyleneuridine (and cytidine) derivatives from uridine ketonucleosides
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Treatment of 3',5'(or 2',5')-bis-O-silyl-protected 2'(or 3')-ketouridine derivatives with methyltriphenylphosphonium bromide and sodium 2-methyl-2-butoxide in diethyl ether/benzene at 0-4 °C resulted in the slow formation of the corresponding 2'(or 3')-deoxy-2'(or 3')-methylene analogues. 1H- and 31P-NMR spectra were in harmony with formation of a single oxaphosphetane diastereoisomer during early stages of the Wittig reaction. Conversions of protected deoxymethyleneuridine to deoxymethylenecytidine derivatives were effected smoothly via 4-(1,2,4-triazol-1-yl) intermediates. Deprotection with tetrabutylammonium fluoride gave 2'(or 3')-deoxy-2'(or 3')-methylneuridine and cytidine nucleosides.
- Samano,Robins
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p. 283 - 288
(2007/10/02)
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- 2'-alkylidenepyrimidine nucleoside derivatives, process for production thereof, and uses thereof
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Disclosed are novel 2'-alkylidenepyrimidine nucleoside derivatives represented by formula [I]: STR1 wherein R1 is an amino gorup or a hydroxy group, R2 is a hydrogen atom, a halogen atom or a lower alkyl group, R3 is a hydrogen atom or a lower alkyl group, and R4 is a hydrogen atom or a phosphate residue, or salts thereof. These novel compounds can be produced from uridine or cytidine derivatives by alkylidenating the 2'-position in the sugar moiety thereof with Wittig's reagent. Furthermore, the compounds have remarkable antiviral activities and therefore can provide novel antiviral agents.
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