Mitochondria-targeted chelators with potential to disrupt iron metabolism in cancer cells: The role of the linker structure in successful membrane translocation.

One of the recent novel approaches to treating cancer involves restricting the bioavailability of iron ions in cancer cells. This can be achieved by using mitochondria-targeted chelators that are selective for iron(III) ions, can cross the plasma and mitochondrial membranes, and thus potentially disrupt mitochondrial respiration. To pass the membrane barrier, the compound must be sufficiently hydrophobic. A series of compounds with a 3-hydroxypyrid-4-one chelating unit (analogues of deferiprone, DFP, one of the clinically approved iron chelators) connected to a mitochondria-targeting triphenylphosphonium (TPP) moiety through linkers of different lengths and compositions was synthesised. The influence of the linker on the overall hydrophobicity of the molecules was studied by determining the octanol/water distribution coefficient. For this purpose, a modified methodology for measuring the octanol/water distribution coefficient with low material consumption, based on HPLC analysis, was developed and validated against the standard UV-Vis technique. No adverse effect of the linker and the phosphonium moiety on the strong chelating ability of the hydroxypyridone group for iron(III) was observed. Preliminary cell studies demonstrate that these chelators can cross biological membranes, and their cytotoxicity increases with increasing hydrophobic character of the linker used. A comparative study of molecules whose iron(III)-binding ability was blocked by modification of the chelating unit showed that general TPP-based membrane disruption and iron(III)-chelating ability cumulate to increase cytotoxicity.