Ruthenium, Titanium and Gallium for Treating Cancer

Abstract

Complexes of ruthenium, Ru, which have been extensively used as metal catalysts for chemical transformations, are also showing considerable promise for the treatment of cancer [1][2][3][4][5][6]. While some of these agents directly attack and kill the primary tumor, others have the interesting property of preventing the tumor from releasing cells that spread to other parts of the body. The structures and properties of these compounds range from traditional coordination compounds that lose ligands by interacting directly with biological targets to organometallic compounds which, in addition to binding to molecular targets, can facilitate the generation of reactive oxygen species, ROSs, which chemically modify biological molecules in the cell. In addition to killing cells through chemical reactivity, some ruthenium compounds express their biological effects by acting as shape-specific inhibitors of enzymes that are important for the survival of the cell. A brief overview of the chemistry and mechanistic aspects of these compounds will be given in this chapter. Chemistry of ruthenium in the biological milieuRuthenium, atomic number 44, has a number of known oxidation states, but only two, Ru þ2 [Kr]4d 6 , a soft acid, and Ru þ3 [Kr]4d 5 , an intermediate acid, have been extensively incorporated into new agents for the treatment of cancer. Both oxidation states prefer six-coordinate octahedral geometry, with the complexes of Ru þ3 , due to its greater charge, having the higher value of CFSE, D. Since ruthenium is in the second-row transition metal series, below iron in the periodic table, most Ru þ3 , t 5 2g , S ¼ 1 / 2 , as well as Ru þ2 , t 6 2g , S ¼ 0, complexes are low-spin. The first-order water exchange rate constants, k, for aquated Ru þ2 and Ru þ3 are $10 À2 (t 1/2 $ 1 minute) and $10 À6 s À1 (t 1/2 $19 hours), respectively, at 25 C (Figure 1.20), with the exchange mechanism most likely being associative (1.23) [7]. As expected, the ion with the higher charge, which has the higher value of D, and thus the greater free energy of activation, DG z , has the smaller exchange rate constant, k, through (1.22). While the exchange rate for aquated Ru þ3 is too slow for reaction of the ion with biological targets, the exchange rate constant of Ru þ2 is about an order of magnitude larger than that of Pt þ2 , suggesting that complexes of Ru þ2 may be better suited for reaction with biological targets in the body. However, as will be evident below, exchange rates for either ion can Metals in MedicineJames C. Dabrowiak vary considerably depending on the nature of the attached ligands. An additional interesting aspect of ruthenium chemistry is that it appears that the two ruthenium oxidation states can be interconverted by substances in the body, suggesting that redox may play an important role in the pharmacology of ruthenium [5]. Although Ru þ4 has been proposed as an intermediate in the reaction of certain Ru þ3 complexes, the tetravalent oxidation state of the metal has been relatively little studied in connection wit...