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

Abstract : 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.
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Mun Juinn Chow, Maria Babak, Daniel Yuan Qiang Wong, Giorgia Pastorin, Christian Gaiddon, et al.. Structural Determinants of p53-Independence in Anticancer Ruthenium-Arene Schiff-Base Complexes. Molecular Pharmaceutics, American Chemical Society, 2016, 13 (7), pp.2543-2554. ⟨10.1021/acs.molpharmaceut.6b00348⟩. ⟨inserm-02365323⟩

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