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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
8
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pubmed:dateCreated |
1988-9-2
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pubmed:abstractText |
A new synthesis of 5-(monofluoromethyl)- and 5-(difluoromethyl)-2'-deoxy-2'-fluoro-beta-D-arabinofuranosyluracil (F-FMAU and F2-FMAU) is reported. 3',5'-Di-O-(tert-butyldiphenyl)silylated thymidine or FMAU was photochemically brominated with NBS to the corresponding alpha-monobromide, which was hydrolyzed to the 5-hydroxymethyl derivative. Further oxidation of the latter with MnO2 afforded the 5-formyluracil nucleoside. Treatment of these nucleosides with DAST in CH2Cl2 gave the protected alpha-fluorinated nucleosides. Desiylation with TBAF afforded the desired free nucleosides. Also, 5-(trifluoromethyl)-2'-deoxy-2'-fluoro-beta-D-arabinofuranosyluracil (F3-FMAU) was synthesized by copper-catalyzed trifluoromethylation of 5-iodo-2'-fluoro-ara-U (FIAU). These new nucleosides were studied in comparison with the corresponding 2'-deoxy-erythro-pentofuranosyl derivatives, for their inhibitory activity against cellular thymidylate synthase (TS) and [3H]TdR incorporation into DNA, cytotoxicity against HL-60 cells, and antiviral activity against herpes simplex types 1 and 2 (HSV-1 and -2). F2-TDR and F3-TDR strongly inhibited TS and were also quite cytotoxic and antiherpetic, whereas FTDR was only active in the antiviral assay. In the 2'-fluoroarabino series, fluorine substitution at the alpha-methyl function did not alter significantly the antiherpetic activity. Although FMAU and F-FMAU did not inhibit TS to any significant extent, F2-FMAU and F3-FMAU were weakly inhibitory. The latter nucleosides did not inhibit [3H]TDR incorporation into DNA, while all the other alpha-fluorinated thymine nucleosides inhibited the incorporation of radioactivity of [3H]TDR into DNA to various extents. F2-FMAU and F3-FMAU were about 2 orders of magnitude less cytotoxic against HL-60 cells than were F2-TDR and F3-TDR. The results strongly suggest that in both the 2'-deoxy-2'-fluoroarabino and the 2'-deoxy-erythro-pentofurano series the cytotoxic action of the alpha,alpha-difluoro and alpha,alpha,alpha-trifluoro derivatives may involve the inhibition of TS. The synthesis of [2-14C]F2-FMAU, as an experimental imaging agent, is also described. Unfortunately, the highly selective uptake of the labeled compound within infected brain regions previously noted with [2-14C]FMAU was not detected with the derivative [2-14C]F2-FMAU.
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pubmed:grant | |
pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/2'-fluoro-5-methylarabinosyluracil,
http://linkedlifedata.com/resource/pubmed/chemical/Antiviral Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Arabinofuranosyluracil,
http://linkedlifedata.com/resource/pubmed/chemical/Deoxyuridine,
http://linkedlifedata.com/resource/pubmed/chemical/Nucleosides,
http://linkedlifedata.com/resource/pubmed/chemical/Thymidylate Synthase,
http://linkedlifedata.com/resource/pubmed/chemical/Uridine
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pubmed:status |
MEDLINE
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pubmed:month |
Aug
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pubmed:issn |
0022-2623
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:volume |
31
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1642-7
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pubmed:dateRevised |
2008-11-21
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pubmed:meshHeading |
pubmed-meshheading:2840503-Animals,
pubmed-meshheading:2840503-Antiviral Agents,
pubmed-meshheading:2840503-Arabinofuranosyluracil,
pubmed-meshheading:2840503-Cell Division,
pubmed-meshheading:2840503-Chemical Phenomena,
pubmed-meshheading:2840503-Chemistry,
pubmed-meshheading:2840503-Deoxyuridine,
pubmed-meshheading:2840503-Encephalitis,
pubmed-meshheading:2840503-Herpes Simplex,
pubmed-meshheading:2840503-Nucleosides,
pubmed-meshheading:2840503-Rats,
pubmed-meshheading:2840503-Simplexvirus,
pubmed-meshheading:2840503-Structure-Activity Relationship,
pubmed-meshheading:2840503-Thymidylate Synthase,
pubmed-meshheading:2840503-Uridine
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pubmed:year |
1988
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pubmed:articleTitle |
Nucleosides. 150. Synthesis and some biological properties of 5-monofluoromethyl, 5-difluoromethyl, and 5-trifluoromethyl derivatives of 2'-deoxyuridine and 2'-deoxy-2'-fluoro-beta-D-arabinofuranosyluracil.
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pubmed:affiliation |
Laboratory of Organic Chemistry, Memorial Sloan-Kettering Cancer Center, Cornell University, New York, New York 10021.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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