MotW16: Anticancer properties of Ruthenium(II) complexes

Ruthenium(II) complexes of the general formula [(η6-arene)Ru(XY)Z]+ were studied for their anticancer properties in A2780 human ovarian cancer cells and A549 human lung cancer cells (Inorg. Chem. 2009, 48, 9444–9453, DOI: 10.1021/ic9013366). The specific arenes used included p-cymene, hexamethylbenzene, and biphenyl), XY denotes o-phenylenediamine, o-benzoquinonediimine or 4,5-dimethyl-o-phenylenediamine, and Z denotes Cl, Br, or I. In particular, redox-active diamine ligands were tested for their inhibitory growth properties for those cancer cells.

The researchers found that when the oxidized ligand (o-bqdi) was present in the Ruthenium complex, it showed no activity in inhibiting the growth of cancer cells. While the ligand (o-pda) showed the highest inhibitory activity against A2780 ovarian cancer cells, none of the complexes showed any activity against the A549 lung cancer cells. The paper states that the presence of GSH in 15-mol equiv reduced complex 4 completely to o-pda from o-bqdi. The o-bqdi chelating ligand, when reduced to an o-pda chelating ligand, acts as an inhibitory complex. However, in human cells, GSH is naturally present in 2-10mM concentrations, which is significantly lower than the 15-mol equiv concentration. Because there was no activity in complex 4 in either cancerous cell, the paper concludes that the reduction process from GSH is too slow. Also, reoxidation from oxygen (air) prevents the reduction to o-pda from taking place.

The authors also state that the low activity of the oxidized chelated ligand may be the result of the stabilizing effect the π-acceptor o-bqdi has on the Ruthenium complex, making it more difficult for Cl- to leave the complex. The Ru-Cl bond does not break as readily resulting in low hydrolysis that is required for reactions with DNA. The hydrolysis of Ru-Cl results in a [(η6-arene)Ru(II)(en)H2O]2+ that binds to DNA and forms a monofunctional adduct. The paper concludes that the low activity of the complexes in inhibiting cancer cells could be a result of a lack of hydrolysis. Hydrolysis allows the complex to form an adduct with the guanine. The ligands and complexes presented are interesting because of their potential cytotoxicity towards cancer cells.

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