Development of Ruthenium Antitumor Drugs that Overcome Multidrug Resistance Mechanisms

Organometallic ruthenium(II) complexes of the general formula [Ru(η6-p-cymene)Cl2(L)] and [Ru(η6-p-cymene)Cl(L)2][BPh4] with modified phenoxazine- and anthracene-based multidrug resistance (MDR)
modulator ligands (L) have been synthesized, spectroscopically characterized, and evaluated in vitro for
their cytotoxic and MDR reverting properties in comparison with the free ligands. For an anthracene-based
ligand, coordination to a ruthenium(II) arene fragment led to significant improvement of cytotoxicity as
well as Pgp inhibition activity. A similar, but weaker effect was also observed when using a benzimidazole-phenoxazine derivative as Pgp inhibitor. The most active compound in terms of both Pgp inhibition and
cytotoxicity is [Ru(η6-p-cymene)Cl2(L)], where L is an anthracene-based ligand. Studies show that it induces
cell death via inhibition of DNA synthesis. Moreover, because the complex is fluorescent, its uptake in
cells was studied, and relative to the free anthracene-based ligand, uptake of the complex is accelerated and
accumulation of the complex in the cell nucleus is observed.