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Development of Ruthenium Antitumor Drugs that Overcome Multidrug Resistance Mechanisms

2007; American Chemical Society; Volume: 50; Issue: 9 Linguagem: Inglês

10.1021/jm070039f

1520-4804

Carsten A. Vock, Wee Han Ang, C. Scolaro, A.D. Phillips, Lucienne Lagopoulos, Lucienne Juillerat‐Jeanneret, Gianni Sava, Rosario Scopelliti, Paul J. Dyson,

Synthesis and Biological Evaluation

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.