Tuning the reactivity of osmium(II) and ruthenium(II) arene complexes under physiological conditions.
The Os(II) arene ethylenediamine (en) complexes [(eta(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 [(eta(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 [(eta(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, [(eta(6)-arene)Os(acac)(OH(2))](+), but also the hydroxo-bridged dimer, [(eta(6)-arene)Os(mu(2)-OH)(3)Os(eta(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 [(eta(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.
Peacock
Anna F A
AF
Contribution from the School of Chemistry, University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ, U.K.
Habtemariam
Abraha
A
Fernández
Rafael
R
Walland
Victoria
V
Fabbiani
Francesca P A
FP
Parsons
Simon
S
Aird
Rhona E
RE
Jodrell
Duncan I
DI
Sadler
Peter J
PJ
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001555:Benzene Derivatives / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D009992:Osmium / Q000737:chemistry*; D010051:Ovarian Neoplasms / Q000188:drug therapy; D012428:Ruthenium / Q000737:chemistry*
D000970:Antineoplastic Agents; D001555:Benzene Derivatives; D009942:Organometallic Compounds; D009992:Osmium; D012428:Ruthenium