Tuning the Reactivity of Osmium(II) and Ruthenium(II) Arene Complexes under Physiological Conditions

The OsII arene ethylenediamine (en) complexes [(η6-biphenyl)Os(en)Cl][Z], Z = BPh4 (4) and BF4 (5), are inactive toward A2780 ovarian cancer cells despite 4 being isostructural with an active RuII analogue, 4R. Hydrolysis of 5 occurred 40 times more slowly than 4R. The aqua adduct 5A has a low pKa (6.3) compared to that of [(η6-biphenyl)Ru(en)(OH2)]2+ (7.7) and is therefore largely in the hydroxo form at physiological pH. The rate and extent of reaction of 5 with 9-ethylguanine were also less than those of 4R. We replaced the neutral en ligand by anionic acetylacetonate (acac). The complexes [(η6-arene)Os(acac)Cl], arene = biphenyl (6), benzene (7), and p-cymene (8), adopt piano-stool structures similar to those of the RuII analogues and form weak dimers through intermolecular (arene)CH···O(acac) H-bonds. Remarkably, these OsII acac complexes undergo rapid hydrolysis to produce not only the aqua adduct, [(η6-arene)Os(acac)(OH2)]+, but also the hydroxo-bridged dimer, [(η6-arene)Os(μ2-OH)3Os(η6-arene)]+. The pKa values for the aqua adducts 6A, 7A, and 8A (7.1, 7.3, and 7.6, respectively) are lower than that for [(η6-p-cymene)Ru(acac)(OH2)]+ (9.4). Complex 8A rapidly forms adducts with 9-ethylguanine and adenosine, but not with cytidine or thymidine. Despite their reactivity toward nucleobases, complexes 68 were inactive toward A549 lung cancer cells. This is attributable to rapid hydrolysis and formation of unreactive hydroxo-bridged dimers which, surprisingly, were the only species present in aqueous solution at biologically relevant concentrations. Hence, the choice of chelating ligand in OsII (and RuII) arene complexes can have a dramatic effect on hydrolysis behavior and nucleobase binding and provides a means of tuning the reactivity and the potential for discovery of anticancer complexes.