title: Cyclosaligenyl pronucleotides of 5-iodo and 5-trifluoromethyl-1-(2-deoxy-beta-D-ribofuranosyl)-2,4-difluorobenzene mimics of thymidine: synthesis and evaluation of this pronucleotide monophosphate delivery system for compounds with potential anticancer activity.
abstract: A group of unnatural 1-(2-deoxy-beta-D-ribofuranosyl)-2,4-difluorobenzenes possessing a 5-I or 5-CF3 substituent, that were originally designed as thymidine mimics, were coupled via their 5'-OH group to a cyclosaligenyl (cycloSal) ring system having a variety of C-3 substituents (Me, OMe, H). The 5'-O-cycloSal-pronucleotide concept was designed to effect a thymidine kinase-bypass, thereby providing a method for the intracellular delivery and generation of the 5'-O-monophosphate for nucleosides that are poorly phosphorylated. The 5'-O-cycloSal pronucleotide phosphotriesters synthesized in this study were obtained as a 1:1 mixture of two diastereomers that differ in configuration (S(P) or R(P)) at the asymmetric phosphorous center. The (S(P))- and (R(P))-diastereomers for the 5'-O-3-methylcycloSal- and 5'-O-3-methoxycycloSal derivatives of 1-(2-deoxy-beta-D-ribofuranosyl)-2,4-difluoro-5-iodobenzene were separated by silica gel flash column chromatography. This class of cycloSal pronucleotide compounds generally exhibited weak cytotoxic activities in a MTT assay (CC50 values in the 10(-3) to 10(-4) M range), against a number of cancer cell lines (143B, 143B-LTK, EMT-6, Hela, 293), except for cyclosaligenyl-5'-O-[1'-(2,4-difluoro-5-iodophenyl)-2'-deoxy-beta-D-ribofuranosyl]phosphate that was more potent (CC50 values in the 10(-5) to 10(-6) M range), than the reference drug 5-iodo-2'-deoxyuridine (IUDR) which showed CC50 values in the 10(-3) to 10(-5) M range.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Wei Yan
authors.initials: WY
authors.lastname: Sun
authors.forename: Aihua
authors.initials: A
authors.lastname: Zhou
authors.forename: Leonard I
authors.initials: LI
authors.lastname: Wiebe
authors.forename: Edward E
authors.initials: EE
authors.lastname: Knaus
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006574:Heterocyclic Compounds, 2-Ring / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology; D013936:Thymidine / Q000031:analogs & derivatives*
chemical_list: D000970:Antineoplastic Agents; D006574:Heterocyclic Compounds, 2-Ring; D009943:Organophosphorus Compounds; D011355:Prodrugs; D013936:Thymidine