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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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-hydoxymethyl 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-FMAC) 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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