Preparative, physico-chemical and cytotoxicity studies of prodrugs activated in hypoxia to give metal-binding analogues of bleomycin
The synthesis of 2,6-disubstituted pyridines 10, 23, 27a–28b is reported. These compounds are expected to complex iron(II) and yield hydroxyl radicals by interaction of the aqueous complex with oxygen. In addition a second series of 2,6-disubstituted pyridines 24a, 24b and 29 having additional features (nitro or N-oxide groups), which are expected to prevent complexation of iron, is described. These deactivated compounds are expected to be reduced in hypoxic tumour cells to yield products 25a, 25b and 10, respectively, which are able to complex metals and yield hydroxyl radicals. EPR and fluorescence spectroscopy provide evidence for the production of hydroxyl radicals from all the compounds except the prodrugs 10, 25a and 25b and the compounds not having an imidazole nucleus 27a–28b. The prodrugs were not cytotoxic in air alone to Chinese hamster V79 cells in vitro. However, when the prodrug was added to the cells and then exposed to hypoxia followed by air, the nitro compounds 24a and 24b showed slightly increased cytotoxicity. However, the N-oxide 29 showed marked cytotoxicity similar to that of the corresponding N-deoxygenated compound 10.