Cationic Ru(η6‐p‐cymene) Complexes of 3‐Hydroxy‐4‐pyr(id)ones – Lipophilic Triphenylphosphine as Co‐Ligand Is Key to Highly Stable and Cytotoxic Anticancer Agents

Ru(arene)[3‐hydroxy‐4(1H)‐pyr(id)one]Cl complexes are known to be converted intodinuclear Ru(arene) compounds with three hydroxido bridges in aqueous solution. In an attempt to obtain anticancer Ru(arene) complexes of 3‐hydroxy‐4(1H)‐pyr(id)one ligands that are stable in aqueous solution, triphenylphosphine (PPh3) and 1,3,5‐triaza‐7‐phoshatricyclo[3.3.1.1]decane (pta) were introduced as co‐ligands instead of the chlorido ligand. This led to a series of cationic complexes that were characterized by using standard methods and X‐ray diffraction analysis. The pta complexes were found to be highly stable in aqueous solution for up to 120 h. While they were unreactive in the presence of l‐histidine (His) and l‐methionine (Met), l‐cysteine (Cys) induced cleavage of the 3‐hydroxy‐4(1H)‐pyr(id)one ligands from the Ru center. In vitro cytotoxicity assays against human cancer cell lines revealed that the complexes with the more lipophilic phosphine ligand were cytotoxic in the low‐micromolar concentration range, while the analogous pta compounds did not significantly inhibit cell proliferation. Replacing the labile chlorido ligand in Ru(η6‐p‐cymene)[3‐hydroxy‐4(1H)‐pyr(id)one]Cl complexes with triphenylphosphine or 1,3,5‐triaza‐7‐phoshatricyclo[3.3.1.1]decane resulted in compounds with higher anticancer activity. The improved activity can be rationalized by higher stability in aqueous solution and in the presence of biomolecules.