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

The antitumor activity of the organometallic ruthenium(II)-arene mixed phosphine complexes, [Ru(h6-p-cymene)Cl(PTA)(PPh3)]BF4 1b and [Ru(h6-C6H5CH2CH2OH)Cl(PTA)(PPh3)]BF4 2b (PTA = 1,3,5-triaza-7-phosphaadamantane), have been evaluated in vitro and compared to their RAPTA analogs, [Ru(h6-p-cymene)Cl2(PTA)] 1a and [Ru(h6-C6H5CH2CH2OH)Cl2(PTA)] 2a. The results show that the addn. 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-tumorigenic 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 compds. with a 14-mer oligonucleotide and the model proteins ubiquitin and cytochrome-c.