title: Synthesis and biological activity of 5-(2,2-difluorocyclopropyl)-2'-deoxyuridine deoxyuridine diastereomers.
abstract: The synthesis of the two diastereomers (9 and 10) of 5-(2,2-difluorocyclopropyl)-2'-deoxyuridine are described. Their antiviral and cytotoxic activities were determined, in comparison with (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) and 5-fluoro-2'-deoxyuridine (FDU), respectively. 5-[(1R)-2,2-Difluorocyclopropyl]-2'-deoxyuridine (10) was the most active antiviral agent against HSV-1 (IC50 = 5 micrograms/ml) relative to BVDU (IC50 = 0.082 micrograms/ml), and cytotoxic agent in the CCRF-CEM (IC50 = 230 microM) screen relative to FDU (IC50 = 4.7 x 10(-3) microM). The 5-[(1S)-2,2-difluorocyclopropyl] diastereomer was inactive in both screens. Partition coefficients (P) and affinity for the mouse erythrocyte nucleoside transporter (Ki) were not determinants of antiviral or cytotoxic activities. However, the (1R)-diastereomer (10) was more resistant to glycosidic bond cleavage by thymidine phosphorylase than the (1S)-diastereomer (9).
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Tandon
authors.forename: S
authors.initials: S
authors.lastname: Singh
authors.forename: L
authors.initials: L
authors.lastname: Xu
authors.forename: P
authors.initials: P
authors.lastname: Kumar
authors.forename: L I
authors.initials: LI
authors.lastname: Wiebe
authors.forename: E E
authors.initials: EE
authors.lastname: Knaus
authors.forename: W P
authors.initials: WP
authors.lastname: Gati
authors.forename: M L
authors.initials: ML
authors.lastname: Tempest
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001973:Bromodeoxyuridine / Q000031:analogs & derivatives / Q000494:pharmacology; D002352:Carrier Proteins / Q000097:blood / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D003857:Deoxyuridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004910:Erythrocyte Membrane / Q000187:drug effects; D008565:Membrane Proteins / Q000097:blood / Q000187:drug effects; D051379:Mice; D033703:Nucleoside Transport Proteins; D018139:Simplexvirus / Q000187:drug effects*; D013237:Stereoisomerism; D010948:Viral Plaque Assay
chemical_list: D000998:Antiviral Agents; D002352:Carrier Proteins; D008565:Membrane Proteins; D033703:Nucleoside Transport Proteins; C053403:5-(2,2-difluorovinyl)-2'-deoxyuridine; C020235:brivudine; D001973:Bromodeoxyuridine; D003857:Deoxyuridine