Impact of the Halogen Substitution Pattern on the Biological Activity of Organoruthenium 8‑Hydroxyquinoline Anticancer Agents

8-Hydroxyquinoline and its derivatives
have a broad variety of
pharmacological properties, which make them an ideal bioactive building
block in the development of metal-based anticancer drugs. In this
account we aimed to rationalize the antiproliferative efficacy of
organoruthenium compounds featuring 8-hydroxyquinoline-derived ligands
and to elucidate structural determinants by using biological assays
and bioanalytical methods. By systematically varying the halide substitution
pattern at the 5- and 7-positions of the 8-hydroxyquinoline ligand,
as well as the halido leaving group, a series of 5,7-dihalido-8-hydroxyquinoline
RuII(η6-p-cymene) complexes
were obtained. Studies on their cytotoxic activity revealed the minor
impact of the substitution pattern (with the exception of complexes
of 8-hydroxyquinoline) on their activity. Notably, the cellular accumulation
showed no correlation with the cytotoxic activity, while the nature
of the halido leaving group only had a significant influence in the
case of the 8-hydroxyquinoline organoruthenium compounds. However,
the compounds were shown to be very stable under a wide variety of
pH conditions, making them possible candidates for further development
as orally active anticancer agents.