Models of hypoxia activated prodrugs: Co(III) complexes of hydroxamic acids

Co(III) complexes of simple hydroxamic acids have been evaluated as models of hypoxia activated prodrugs containing MMP inhibitors. The complexes are based upon a proposed carrier system comprising the tripodal tetradentate ligand tris(2-methylpyridyl)amine (tpa) with the hydroxamate functionality occupying the remaining coordination sites of the Co centre. Acetohydroxamato (aha), propionhydroxamato (pha), and benzohydroxamato (bha) complexes were synthesised and characterised by single crystal X-ray diffraction. For aha and pha both the hydroxamato and hydroximato (deprotonated) forms were obtained and were readily interconverted by pH manipulation; for bha only the hydroximato complex was obtained as a stable species. Electrochemical analysis was used to probe the redox chemistry of the complexes and assess their ease of reduction. All of the complexes displayed irreversible reduction and had low cathodic peak potentials. This suggests that the Co-tpa carrier system would provide a suitably inert framework to deliver the drugs to target sites intact yet would release the ligands upon reduction to the more labile Co(II) oxidation state.