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. T hese compounds are expected to complex iron(II) and yield hydroxyl radicals by interaction of the aqueous complex with oxygen. In addition a second se ries of 2,6-disubstituted pyridines 24a, 24b and 29 having additional featu res (nitro or N-oxide groups), which are expected to prevent complexation o f iron, is described. These deactivated compounds are expected to be reduce d in hypoxic tumour cells to yield products 25a, 25b and 10, respectively, which are able to complex metals and yield hydroxyl radicals. EPR and fluor escence spectroscopy provide evidence for the production of hydroxyl radica ls from all the compounds except the prodrugs 10, 25a and 25b and the compo unds not having an imidazole nucleus 27a-28b. The prodrugs were not cytotox ic in air alone to Chinese hamster V79 cells in vitro. However, when the pr odrug was added to the cells and then exposed to hypoxia followed by air, t he nitro compounds 24a and 24b showed slightly increased cytotoxicity. Howe ver, the N-oxide 29 showed marked cytotoxicity similar to that of the corre sponding N-deoxygenated compound 10.