Synthesis, hydroxyl radical production and cytotoxicity of analogues of bleomycin.
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.
Highfield
J A
JA
Institute for Physical and Environmental Sciences, Brunel University, Uxbridge, Middlesex, UK.
Mehta
L K
LK
Parrick
J
J
Wardman
P
P
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*
D001761:Bleomycin; D017665:Hydroxyl Radical