Structural Determinants of p53-Independence in Anticancer Ruthenium-Arene Schiff-Base Complexes

p53
is a key tumor suppressor gene involved in key cellular processes
and implicated in cancer therapy. However, it is inactivated in more
than 50% of all cancers due to mutation or overexpression of its negative
regulators. This leads to drug resistance and poor chemotherapeutic
outcome as most clinical drugs act via a p53-dependent mechanism of
action. An attractive strategy to circumvent this resistance would
be to identify new anticancer drugs that act via p53-independent mode
of action. In the present study, we identified 9 Ru (II)-Arene Schiff-base
(RAS) complexes able to induce p53-independent cytotoxicity and discuss
structural features that are required for their p53-independent activity.
Increasing hydrophobicity led to an increase in cellular accumulation
in cells with a corresponding increase in efficacy. We further showed
that all nine complexes demonstrated p53-independent activity. This
was despite significant differences in their physicochemical properties,
suggesting that the iminoquinoline ligand, a common structural feature
for all the complexes, is required for the p53-independent activity.