Photoactivatable Organometallic Pyridyl Ruthenium(II) Arene Complexes

The synthesis and characterization of a family of piano-stool Ru^II arene complexes of the type [(η⁶-arene)­Ru­(N,N′)­(L)]­[PF₆]₂, where arene is <i>p</i>-cymene (<i>p</i>-cym), hexamethylbenzene (hmb), or indane (ind), N,N′ is 2,2′-bipyrimidine (bpm), 1,10-phenanthroline (phen), 1,10-phenanthroline-5,6-dione (phendio), or 4,7-diphenyl-1,10-phenanthroline (bathophen), and L is pyridine (Py), 4-methylpyridine (4-MePy), 4-methoxypyridine (4-MeOPy), 4,4′-bipyridine (4,4′-bpy), 4-phenylpyridine (4-PhPy), 4-benzylpyridine (4-BzPy), 1,2,4-triazole (trz), 3-acetylpyridine (3-AcPy), nicotinamide (NA), or methyl nicotinate (MN), are reported, including the X-ray crystal structures of [(η⁶-<i>p</i>-cym)­Ru­(bpm)­(4-MePy)]²⁺ (<b>2</b>), [(η⁶-<i>p</i>-cym)­Ru­(bpm)­(4-BzPy)]²⁺ (<b>6</b>), [(η⁶-<i>p</i>-cym)­Ru­(bpm)­(trz)]²⁺ (<b>7</b>), [(η⁶-<i>p</i>-cym)­Ru­(phen)­(Py)]²⁺ (<b>10</b>), and [(η⁶-ind)­Ru­(bpy)­(Py)]²⁺ (<b>13</b>). These complexes can selectively photodissociate the monodentate ligand (L) when excited with UVA or white light, allowing strict control of the formation of the reactive aqua species [(η⁶-arene)­Ru­(N,N′)­(OH₂)]²⁺ that otherwise would not form in the dark. The photoproducts were characterized by UV–vis absorption and ¹H NMR spectroscopy. DFT and TD-DFT calculations were employed to characterize the excited states and to obtain information on the photochemistry of the complexes. All the Ru^II pyridine complexes follow a relatively similar photochemical L-ligand dissociation mechanism, likely to occur from a series of ³MC triplet states with dissociative character. The photochemical process proved to be much more efficient when UVA-range irradiation was used. More strikingly, light activation was used to phototrigger binding of these potential anticancer agents with discriminating preference toward 9-ethylguanine (9-EtG) over 9-ethyladenine (9-EtA). Calf thymus (CT)-DNA binding studies showed that the irradiated complexes bind to CT-DNA, whereas the nonirradiated forms bind negligibly. Studies of CT-DNA interactions in cell-free media suggest combined weak monofunctional coordinative and intercalative binding modes. The Ru^II arene complexes [(η⁶-<i>p</i>-cym)­Ru­(bpm)­(Py)]²⁺ (<b>1</b>), [(η⁶-<i>p</i>-cym)­Ru­(bpm)­(4-MeOPy)]²⁺ (<b>3</b>), [(η⁶-<i>p</i>-cym)­Ru­(4,4′-bpy)]²⁺ (<b>4</b>), [(η⁶-hmb)­Ru­(bpm)­(Py)]²⁺ (<b>8</b>), [(η⁶-ind)­Ru­(bpm)­(Py)]²⁺ (<b>9</b>), [(η⁶-<i>p</i>-cym)­Ru­(phen)­(Py)]²⁺ (<b>10</b>), [(η⁶-<i>p</i>-cym)­Ru­(bathophen)­(Py)]²⁺ (<b>12</b>), [(η⁶-<i>p</i>-cym)­Ru­(bpm)­(NA)]²⁺ (<b>15</b>), and [(η⁶-<i>p</i>-cym)­Ru­(bpm)­(MN)]²⁺ (<b>16</b>) were cytotoxic toward A2780 human ovarian cancer cell line in the absence of photoirradiation (IC₅₀ values in the range of 9.0–60 μM)