SYNTHESIS OF 1-(2-DEOXY-β-D-RIBOFURANOSYL)-2,4-DIFLUORO-5-SUBSTITUTED-BENZENES1*: “THYMINE REPLACEMENT” ANALOGS OF THYMIDINE FOR EVALUATION AS ANTICANCER AND ANTIVIRAL AGENTS

Abstract

A group of unnatural 1-(2-deoxy-β-D-ribofuranosyl)-2,4-difluoro-benzenes having a variety of C-5 two-carbon substituents [−C≡C−X, X = I, Br; −C≡CH;(E)−CH=CH−X, X = I, Br; −CH=CH2; −CH2CH3; −CH(N3) CH2Br], designed as nucleoside mimics, were synthesized for evaluation as anticancer and antiviral agents. The 5-substituted (E)−CH=CH−I and −CH2CH3 compounds exhibited negligible cytotoxicity in a MTT assay (CC50 = 10−3 to 10−4 M range), relative to thymidine (CC50 = 10−3 to 10−5 M range), against a variety of cancer cell lines. In contrast, the C-5 substituted −C≡C−I and −CH(N3)CH2Br compounds were more cytotoxic (CC50 = 10−5 to 10−6 M range). The −C≡C−I and −CH2CH3 compounds exhibited similar cytotoxicity against non-transfected (KBALB, 143B) and HSV-1 TK+ gene transfected (KBALB-STK, 143B-LTK) cancer cell lines expressing the herpes simplex virus type 1 (HSV-1) thymidine kinase gene (TK+). This observation indicates that expression of the viral TK enzyme did not provide a gene therapeutic effect. The parent group of 5-substituted compounds, 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-2) viruses], showed that this class of unnatural C-aryl nucleoside mimics are inactive and/or weakly active antiviral agents.