title: Synthesis of unnatural 7-substituted-1-(2-deoxy-beta-D-ribofuranosyl)isocarbostyrils: "thymine replacement" analogs of deoxythymidine for evaluation as antiviral and anticancer agents.
abstract: A group of unnatural 1-(2-deoxy-beta-D-ribofuranosyl)isocarbostyrils having a variety of C-7 substituents [H, 4,7-(NO2)2, I, CF3, CN, (E)-CH=CH-I, -C triple bond CH, -C triple bond C-I, -C triple bond C-Br, -C=C-Me], designed as nucleoside mimics, were synthesized for evaluation as anticancer and antiviral agents. This class of compounds exhibited weak cytotoxicity in a MTT assay (CC50 = 10(-3) to 10(-5) M range) with the 4,7-dinitro derivative being the most cytotoxic, relative to thymidine (CC50 = 10(-3) to 10(-5) M range), against a variety of cancer cell lines. The 4,7-dinitro, 7-I and 7-C triple bond CH compounds exhibited similar cytotoxicity against non-transfected (KBALB, 143B), and HSV-1 TK+ gene transfected (KBALB-STK, 143B-LTK) cancer cell lines possessing the herpes simplex virus type 1 (HSV-1) thymidine kinase gene (TK+). This observation indicates that these compounds are not substrates for HSV type-1 TK, and are therefore unlikely to be useful in gene therapy based on the HSV gene therapy paradigm.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Naimi
authors.forename: W
authors.initials: W
authors.lastname: Duan
authors.forename: L I
authors.initials: LI
authors.lastname: Wiebe
authors.forename: E E
authors.initials: EE
authors.lastname: Knaus
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004261:DNA Replication / Q000187:drug effects; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D013936:Thymidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D016588:Anticarcinogenic Agents; D000998:Antiviral Agents; D007546:Isoquinolines; C008179:isocarbostyril; D013936:Thymidine