Synthesis of 1-(2-deoxy-beta-D-ribofuranosyl)-2,4-difluoro-5-substituted-benzenes: "thymine replacement" analogs of thymidine for evaluation as anticancer and antiviral agents.
A group of unnatural 1-(2-deoxy-beta-D-ribofuranosyl)-2,4-difluorobenzenes 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.
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; D001555:Benzene Derivatives / 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* / Q000737:chemistry; D009705:Nucleosides / Q000737:chemistry; D018139:Simplexvirus / Q000187:drug effects; D013936:Thymidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism; D013941:Thymine / Q000737:chemistry*; D014162:Transfection; D014616:Vaccinia virus / Q000187:drug effects; D014721:Vesicular stomatitis Indiana virus / Q000187:drug effects
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D001555:Benzene Derivatives; D009005:Monosaccharides; D009705:Nucleosides; D013937:Thymidine Kinase; D013941:Thymine; D013936:Thymidine