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

摘要

The Os~Ⅱ arene ethylenediamine (en) complexes [(η~6-biphenyl)Os(en)Cl][Z], Z = BPh_4 (4) and BF_4 (5), are inactive toward A2780 ovarian cancer cells despite 4 being isostructural with an active Ru~Ⅱ analogue, 4R. Hydrolysis of 5 occurred 40 times more slowly than 4R. The aqua adduct 5A has a low pK_a (6.3) compared to that of [(η~6-biphenyl)Ru(en)(OH_2)]~(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 [(η~6-arene)Os(acac)-Cl], arene = biphenyl (6), benzene (7), and p-cymene (8), adopt piano-stool structures similar to those of the Ru~Ⅱ analogues and form weak dimers through intermolecular (arene)C—H...O(acac) H-bonds. Remarkably, these Os~Ⅱ acac complexes undergo rapid hydrolysis to produce not only the aqua adduct, [(η~6-arene)Os(acac)(OH_2)]~+, but also the hydroxo-bridged dimer, [(η~6-arene)Os(μ~2-OH)_3Os(η~6-arene)]~+. The pK_a values for the aqua adducts 6A, 7A, and 8A (7.1, 7.3, and 7.6, respectively) are lower than that for [(η~6-p-cymene)Ru(acac)(OH_2)]~+ (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 Os~Ⅱ (and Ru~Ⅱ) 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.