Tuning the Hydrolytic Aqueous Chemistry of Osmium Arene Complexes with N,O-Chelating Ligands to Achieve Cancer Cell Cytotoxicity

Potential biological and medical applications of organometallic complexes are hampered by a
lack of knowledge of their aqueous solution chemistry. We show that the hydrolytic and aqueous solution
chemistry of half-sandwich OsII arene complexes of the type [(η6-arene)Os(XY)Cl] can be tuned with XY
chelating ligands to achieve cancer cell cytoxicity comparable to carboplatin. Complexes containing arene
= p-cymene, XY = N,O-chelating ligands glycinate (1), l-alaninate (2), α-aminobutyrate (3), β-alaninate
(4), picolinate (5), or 8-hydroxyquinolinate (7) were synthesized. Although, 1−4 and 7 hydrolyzed rapidly
(5 and 6) hydrolyzed
much more slowly (t1/2 = 0.20 and 0.52 h, 298 K). The aqua picolinate complexes were more acidic (pKa*
= 6.67, 6.33) than the other aqua adducts (pKa* = 7.17−7.71). At biological test concentrations (micromolar),
the chelating ligands dissociated from complexes 1−4 to give the inert hydroxo-bridged dinuclear species
[(η6-arene)Os(μ-OH)3Os(η6-arene)]+ (8), and these complexes were inactive toward human lung A549 and
ovarian A2780 cancer cells. In contrast, 5−7 were cytotoxic, especially 6 (IC50 values of 8 and 4.2 μM).
The X-ray structures of 9-ethylguanine, [(η6-p-cym)Os(pico)(9EtG-N7)]PF6, and 9-ethyladenine, [(η6-p-cym)Os(pico)(9EtA-N7)]PF6, adducts of 5 are reported (the first reported for G or A adducts of OsII). Crystals of
the 9EtA complex contain homoadenine base pairing. The 9EtG adduct in particular exhibits remarkable
aqueous kinetic stability. This work shows how the rational control of chemical reactivity (hydrolysis, acidity,
formation of hydroxo-bridged dinuclear species) can allow the design of cytotoxic anticancer OsII arene
complexes.