Synthesis of 1‐(2‐deoxy‐β‐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

Abstract

AbstractA group of unnatural 1‐(2‐deoxy‐β‐D‐ribofuranosyl)‐2,4‐difluorobenzenes having a variety of C‐5 substituents, designed as thymidine mimics, were synthesized for evaluation as antiviral and anticancer agents. The regiospecific addition of HOBr (generated from N‐bromosuccinimide in aqueous dioxane) across the 5‐vinyl substituent (4) afforded the corresponding 5‐[‐CH(OH)CH2Br] product (5), whereas reaction of 4 with iodine in the presence of iodic 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 product (8). The 5‐[‐CH(OMe)CH2I] compound (7) was prepared by reaction of the 5‐vinyl compound (4) with ICl in MeOH (MeOI). This group of compounds (5–8, 11, 12) showed similar (marginal) activity against varicella‐zoster virus thymidine kinase positive (VZV/TK+) and thymidine kinase deficient (VZV/TK–) infected cells. Thus, the viral TK enzyme did not provide a gene therapeutic effect. This group of compounds, which were evaluated using a wide variety of antiviral assay systems [(herpes simplex virus HSV‐1, HSV‐2), varicella‐zoster virus (VZV), vaccinia virus, vesicular stomatitis, cytomegalovirus (CMV), and human immunodeficiency virus (HIV‐1, HIV‐2)], showed that these unnatural C‐aryl nucleoside mimics are inactive antiviral agents. Their failure to exhibit antiviral/anticancer activity could be due to the fact that they are not phosphorylated to the 5′‐monophosphate, or that incorporation of the active 5′‐triphosphate into DNA does not produce a cytotoxic effect, and/or that these C‐aryl nucleoside mimics do not act as inhibitors of thymidylate synthase, which may be required to produce a cytotoxic effect. Drug Dev. Res. 52:492–499, 2001. © 2001 Wiley‐Liss, Inc.