Synthesis of 1-(2-deoxy-beta-D-ribofuranosyl)-2,4-difluoro-5-substituted-benzene thymidine mimics, some related alpha-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, Cl, Br, I, CF3, CN, NO2, NH2), designed as thymidine mimics, were synthesized for evaluation as anticancer and antiviral agents. The coupling reaction of 3,5-bis-O-(p-chlorobenzoyl)-2-deoxy-alpha-D-ribofuranosyl chloride with an organocadmium reagent [(2,4-difluorophenyl)2Cd] afforded a mixture of the alpha- and beta-anomeric products (alpha:beta = 3:1 to 10:1 ratio). Treatment of the alpha-anomer with BF3.Et2O in nitroethane at 110-120 degrees C 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, Cl, I, NH2) beta-anomers exhibited negligible cytotoxicity in a MTT assay (CC50 = 10(-3)-10(-4) M range), relative to thymidine (CC50 = 10(-3)-10(-5) M range), against a variety of cancer cell lines. In contrast, the 5-NO2 derivative was more cytotoxic (CC50 = 10(-5)-10(-6) M range). A number of 5-substituted beta-anomers, and some related alpha-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-2) viruses], showed that this class of unnatural C-aryl nucleoside mimics are inactive antiviral agents.
Wang
Z X
ZX
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
Duan
W
W
Wiebe
L I
LI
Balzarini
J
J
De Clercq
E
E
Knaus
E E
EE
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003587:Cytomegalovirus / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006678:HIV / Q000187:drug effects; D014645:Herpesvirus 3, Human / Q000187:drug effects; D006801:Humans; D018716:Molecular Mimicry; D009005:Monosaccharides / Q000138:chemical synthesis* / Q000494:pharmacology; D018139:Simplexvirus / Q000187:drug effects; D013936:Thymidine / Q000737:chemistry*; D014407:Tumor Cells, Cultured; D014616:Vaccinia virus / Q000187:drug effects; D014721:Vesicular stomatitis Indiana virus / Q000187:drug effects
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D009005:Monosaccharides; D013936:Thymidine