Tuning the hydrophobicity of ruthenium(II)-arene (RAPTA) drugs to modify uptake, biomolecular interactions and efficacy

The antitumour activity of the organometallic ruthenium(ii)-arene mixed phosphine complexes, Ru(eta(6)-p-cymene)Cl(PTA)(PPh(3))]BF(4) and Ru(eta(6)-C(6)H(5)CH(2)CH(2)OH)Cl(PTA)(PPh(3))]BF(4) (PTA = 1,3,5-triaza-7-phosphaadamantane), have been evaluated in vitro and compared to their RAPTA analogues, Ru(eta(6)-p-cymene)Cl(2)(PTA)] and Ru(eta(6)-C(6)H(5)CH(2)CH(2)OH)Cl(2)(PTA)] . The results show that the addition of the PPh(3) ligand to increases the cytotoxicity towards the TS/A adenocarcinoma cancer cells, which correlates with increased uptake, but also increases cytotoxicity to non-tumourigenic HBL-100 cells, thus decreasing selectivity. The decrease in selectivity has been correlated to increased DNA interactions relative to proteins, demonstrated by reactivity of the compounds with a 14-mer oligonucleotide and the model proteins ubiquitin and cytochrome-c.