Synthesis of 1-(2-deoxy-beta-D-ribofuranosyl)-2,4-difluoro-5-(2-halo-1-hydroxyethyl)benzenes and related derivatives: "Thymine replacement" analogs of deoxythymidine for evaluation as antiviral and anticancer agents

A group of unnatural 1-(2-deoxy-beta -D-ribofuranosyl)-2,4-difluorobenzenes having a variety of C-5 substituents, designed as thymidine mimics, were s ynthesized for evaluation as antiviral and anticancer agents. The regiospec ific addition of HOBr (generated from N-bromosuccinimide in aqueous dioxane ) across the 5-vinyl substituent (4) afforded the corresponding 5-[-CH(OH)C H2Br] product (5), whereas reaction of 4 with iodine in the presence of iod ic acid (HOI) yielded the 5-[CH(OH)CH2I] product (6). The related 5-[-CH(OH )CHX2 (X = Br, I)] analogs (11, 12) were similarly prepared from the (E)-5- (2-halovinyl) precursors (9, 10). Treatment of the 5-[-CH(OH)CH2X (X = Br, I)] compounds (5, 6) with NaOH in aqueous dioxane afforded the 5-oxiranyl p roduct (8). The 5-[-CH(OMe)CH2I] compound (7) was prepared by reaction of t he 5-vinyl compound (4) with ICI in MeOH (MeOI). This group of compounds (5 -8, 11, 12) showed similar (marginal) activity against varicella-zoster vir us thymidine kinase positive (VZV/TK+) and thymidine kinase deficient (VZV/ TK-) infected cells. Thus, the viral TK enzyme did not provide a gene thera peutic effect. This group of compounds, which were evaluated using a wide v ariety of antiviral assay systems [(herpes simplex virus HSV-1, HSV-2), var icella-zoster virus (VZV), vaccinia virus, vesicular stomatitis, cytomegalo virus (CMV), and human immunodeficiency virus (HIV-1, HIV-2)], showed that these unnatural C-aryl nucleoside mimics are inactive antiviral agents. The ir failure to exhibit antiviral/anticancer activity could be due to the fac t that they are not phosphorylated to the 5 ' -monophosphate, or that incor poration of the active 5 ' -triphosphate into DNA does not produce a cytoto xic effect, and/or that these C-aryl nucleoside mimics do not act as inhibi tors of thymidylate synthase, which may be required to produce a cytotoxic effect. (C) 2001 Wiley-Liss, Inc.