A potential approach for activating
prodrugs in hypoxic regions of
tumors is to use ionizing radiation, rather than bioreductive
enzymes, to effect reduction. This study investigates radiolytic release of
8-hydroxyquinoline (8-HQ), as a model for hydroxyaza-chloromethylbenzindoline
DNA minor groove
alkylators, from Co(III) complexes under
hypoxia. 8-HQ release, measured by HPLC, showed higher efficiency (one-electron stoichiometry) when the auxiliary
ligand was a tetraazamacrocycle [e.g.
1,4,7,10-tetraazacyclododecane (
cyclen)] rather than a triazamacrocycle [1,4,7-
triazacyclononane (TACN)]. These complexes differ from the bioreductive
cobalt complex
SN 24771 in that their reduction provides stable
cobalt-containing products rather than free (aquated) Co(2+). Radiolytic release of 8-HQ from Co(cyclen)(8-HQ) and Co(TACN)(CN)(8-HQ) was also demonstrated in deoxygenated human plasma, selectively in the absence of
oxygen, again with higher efficiency for the
cyclen system. The
cobalt complexes were >1000-fold less potent than free 8-HQ as inhibitors of cell proliferation and were metabolically stable in aerobic and hypoxic cell cultures. Investigation of cell uptake of total
cobalt, by inductively coupled plasma mass spectrometry, showed that these complexes enter cells but do not accumulate to the high concentrations seen with
SN 24771. The results demonstrate the feasibility of masking the cytotoxicity of hydroxyquinoline-based
cytotoxins as Co(III) complexes and demonstrate the utility of
cyclen-based auxiliary
ligands for optimizing radiolytic activation of these novel
prodrugs under
hypoxia.