Synthesis of 1-(2-deoxy-β-D-ribofuranosyl)-2,4-difluoro-5-substituted-benzene thymidine mimics, some related α-anomers, and their 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 (H, Me, F, CI, Br, I, CF(3), CN, NO(2), NH(2)), designed as thymidine mimics, were synthesized for evaluation as anticancer and antiviral agents. The coupling reaction of 3,5-bis-0-(p-chlorobenzoyl)-2-deoxy-alpha -D-ribofuranosyl chloride with an organocadmium reagent [(2,4-difluorophenyl)(2)Cd] afforded a mixture of the alpha- and beta -anomeric products (alpha:beta = 3:1 to 10:1 ratio). Treatment of the alpha -anomer with BF(3). Et(2)O in nitroethane at 110-120 degreesC for 30 min was developed as an efficient method for epimerization of the major alpha -anomer to the desired beta -anomer. The 5-substituted (H, Me, CI, I, NH(2)) beta -anomers exhibited negligible cytotoxicity in a MTT assay (CC(50) = 10(-3)-10(-4) M range), relative to thymidine (CC(50) = 10(-3)-10(-5) M range), against a variety of cancer cell lines. In contrast, the 5-NO(2) derivative was more cytotoxic (CC(50) = 10(-5)-10(-6) M range). A number of 5-substituted beta -anomers, and some related ol-anomers, that were evaluated using a wide variety of antiviral assay systems [HSV-1, HSV-2, varicella-zoster virus (VZV), vaccinia virus, vesicular stomatitis, cytomegalovirus (CMV) and human immunodeficiency (HIV-1, HIV-3,) viruses], showed that this class of unnatural C-aryl nucleoside mimics are inactive antiviral agents.