title: 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.
abstract: 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.
authors.affiliation: Laboratory of Organic Chemistry, Memorial Sloan-Kettering Cancer Center, Cornell University, New York, New York 10021.
authors.forename: J
authors.initials: J
authors.lastname: Matulic-Adamic
authors.forename: K
authors.initials: K
authors.lastname: Takahashi
authors.forename: T C
authors.initials: TC
authors.lastname: Chou
authors.forename: H
authors.initials: H
authors.lastname: Gadler
authors.forename: R W
authors.initials: RW
authors.lastname: Price
authors.forename: A R
authors.initials: AR
authors.lastname: Reddy
authors.forename: T I
authors.initials: TI
authors.lastname: Kalman
authors.forename: K A
authors.initials: KA
authors.lastname: Watanabe
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D003857:Deoxyuridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D004660:Encephalitis / Q000000981:diagnostic imaging; D006561:Herpes Simplex / Q000000981:diagnostic imaging; D009705:Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology; D011877:Radionuclide Imaging; D051381:Rats; D018139:Simplexvirus / Q000187:drug effects; D013329:Structure-Activity Relationship; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors; D014529:Uridine / Q000031:analogs & derivatives*
chemical_list: D000998:Antiviral Agents; D009705:Nucleosides; D001086:Arabinofuranosyluracil; D013940:Thymidylate Synthase; C034935:clevudine; D003857:Deoxyuridine; D014529:Uridine