title: Synthesis, hydroxyl radical production and cytotoxicity of analogues of bleomycin.
abstract: Two pyridine analogues of the metal complexing region of the anticancer drug bleomycin and two related but deactivated prodrugs have been linked to a 2,6-diphenylpyridine derivative as a DNA binding unit. The 2,6-diphenylpyridine system is structurally related to known amplifiers of the cytotoxicity of bleomycin. The conjugates were found to bind to DNA more strongly than bleomycin-A2 and were more cytotoxic than the corresponding compounds lacking the DNA binding unit. On exposure of a mixture of cells and prodrugs to hypoxia and then air, the prodrug containing the nitrohistidine unit was not bioreductively activated but the prodrug having an N-oxide group was bioreductively activated. This result represents a novel approach to the improvement of the therapeutic ratio of bleomycin analogues.
authors.affiliation: Institute for Physical and Environmental Sciences, Brunel University, Uxbridge, Middlesex, UK.
authors.forename: J A
authors.initials: JA
authors.lastname: Highfield
authors.forename: L K
authors.initials: LK
authors.lastname: Mehta
authors.forename: J
authors.initials: J
authors.lastname: Parrick
authors.forename: P
authors.initials: P
authors.lastname: Wardman
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000031:analogs & derivatives / Q000138:chemical synthesis*; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D017665:Hydroxyl Radical / Q000737:chemistry*
chemical_list: D001761:Bleomycin; D017665:Hydroxyl Radical