- Derivatives of 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-phenyluracil and 5-benzyluracil synthesis and biological properties
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A number of 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)uracil and -cytosine nucleosides substituted at the 5 position with a nitrophenyl or nitrobenzyl group were synthesized from 5-phenyl- and 5-benzyluracil via condensation of the fluorinated sugar, followed by nitration. The corresponding amino analogues were also prepared by reduction of the nitro nucleosides. The uracil nucleosides were converted into the corresponding cytosine nucleosides by way of the triazole intermediates. None of these nucleosides exhibited significant activity against herpes simplex virus type 1 in Vero cells. However, cytosine nucleosides containing the o-nitrophenyl, p-nitrophenyl, p- nitrobenzyl or p-aminobenzyl substituent were found to be toxic (even at 1 μM) to uninfected Vero cells, although they were essentially nontoxic in HL- 60 cells. The 5'-monophosphates of the uracil nucleosides were inhibitors of the reaction catalyzed by purified Ehrlich ascites carcinoma thymidylate synthase, the 5-phenyluracil nucleotides causing a strong inhibition, competitive vs dUMP, described by the K(i) value of 0.01 μM.
- Dziewiszek,Schinazi,Chou,Su,Dzik,Rode,Watanabe
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- Synthesis and biological properties of 5-o-carboranyl-1-(2-deoxy-2- fluoro-β-D-arabinofuranosyl)uracil
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A novel 5-o-carboranyl-containing nucleoside, 5-o-carboranyl-1-(2-deoxy- 2-fluoro-β-D-arabinofuranosyl)uracil (6, CFAU), was synthesized as a potential intracellular neutron capture agent. This compound was prepared in five steps starting from 5-iodo-1-(2
- Fulcrand-El Kattan,Goudgaon,Ilksoy,Huang,Watanabe,Sommadossi,Schinazi
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p. 2583 - 2588
(2007/10/02)
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- Acid-stable 2'-fluoro purine dideoxynucleosides as active agents against HIV
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2',3'-Dideoxy purine nucleosides have anti-HIV activity in vitro and the inosine analogue is being clinically evaluated. The instability of these compounds toward acidic conditions complicates oral administration. The effect of the addition of a fluorine atom to the 2'-position was investigated by preparing the fluorine-containing 2'-erythro and 2'-threo isomers of ddA and the threo of isomer ddI. All fluorine-containing compounds were indefinitely stable to acidic conditions which completely decomposed ddI (1) and ddA (2) in minutes. While the fluorine-containing erythro isomer, 5, was inactive, the threo isomers, 2'-F-dd-ara-A (3) and 2'-F-dd-ara-I (4), were just as potent and active in protecting CD4+ ATH8 cells from the cytopathogenic effects of HIV-1 as the parent drugs. Exposure to pH1 at 37°C prior to testing destroyed the activity of ddA and ddI but left the anti-HIV properties of 3 and 4 unchanged. The fluorinated analogues also protected cells exposed to HIV-2 and inhibited gag gene product expression but not as effectively as the parent compounds. The fluorine-containing analogues appear to be somewhat more toxic in vitro to the antigen- and mitogen-driven proliferation of immunocompetent cells than their corresponding parent compounds.
- Marquez,Tseng,Mitsuya,Aoki,Kelley,Ford Jr.,Roth,Broder,Johns,Driscoll
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p. 978 - 985
(2007/10/02)
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- Nucleosides. 136. Synthesis and antiviral effects of several 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-alkyluracils. Some structure-activity relationships
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In order to study structure-activity relationships between antiherpetic activity and the size of the C-5 alkyl substituents of 2'-fluoro-ara-U derivatives, six new nucleosides (1c-h) were synthesized. The 5-allyl analogue 1c was prepared by a Pd(II)-catal
- Su,Watanabe,Schinazi,Fox
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p. 151 - 154
(2007/10/02)
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- Nucleosides. 129. Synthesis of antiviral nucleosides: 5-alkenyl-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)uracils.
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Synthesis of 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)uracils containing a vinyl (4a), 2-halovinyl (4b-d), or ethyl substituent at C-5 was achieved. These nucleosides were found to be about a log order less active than 2'-fluoro-5-iodo-ara-C (FIAC) aga
- Watanabe,Su,Reichman,Greenberg,Lopez,Fox
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- Nucleosides. 123. Synthesis of Antiviral Nucleosides: 5-Substituted 1-(2-Deoxy-2-halogeno-β-D-arabinofuranosyl)cytosines and -uracils. Some Structure-Activity Relationships
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The syntheses of several 2'-halogeno-5-substituted-arabinofuranosylcytosines and -uracils are described, and relationships of structure to anti herpes virus activity in vitro were examined.Those arabinonucleosides containing the 2'-fluoro function exhibit
- Watanabe, Kyoichi A.,Su, Tsann-Long,Klein, Robert S.,Chu, Chung K.,Matsuda, Akira,et al.
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p. 152 - 156
(2007/10/02)
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