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

Abstract

The antitumour activity of the organometallic ruthenium(II)–arene mixed phosphine complexes, [Ru(η⁶-p-cymene)Cl(PTA)(PPh₃)]BF₄1b and [Ru(η⁶-C₆H₅CH₂CH₂OH)Cl(PTA)(PPh₃)]BF₄2b (PTA = 1,3,5-triaza-7-phosphaadamantane), have been evaluated in vitro and compared to their RAPTA analogues, [Ru(η⁶-p-cymene)Cl₂(PTA)] 1a and [Ru(η⁶-C₆H₅CH₂CH₂OH)Cl₂(PTA)] 2a. The results show that the addition of the PPh₃ ligand to 2a 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.