Nucleosides. 150. Synthesis and Some Biological Properties of 5-Monofluoromethyl, 5-Difluoromethyl, and 5-Trifluoromethyl Derivatives of 2′-Deoxyuridine and 2′-Deoxy-2′-fluoro-β-D-arabinofuranosyluracilt

A new synthesis of 5-(monofluoromethyl)- and 5-(difluoromethyl)-2′-deoxy-2′-fluoro-β-D-arabmofuranosyluracil (F-FMAU and F2-FMAU) is reported. 3′.5′-Di-O-tert-butyldiphenyl)silylated thymidine or FMAU was photochemicaUy brominated with NBS to the corresponding -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 -fluorinated nucleosides. Desiylation with TBAF afforded the desired free nucleosides. Also, 5-(trifluoromethyl)-2′,-deoxy-2′,-fluoro-β-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 -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 -fluorinated thymine nucleosides inhibited the incorporation of radioactivity of [³H]TDR into DNA to various extents. F₂-FMAU and FS-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 theα,α-difluoro and α,α,α-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.