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 6−8 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.