Dual Triggering of DNA Binding and Fluorescence via Photoactivation of a Dinuclear Ruthenium(II) Arene Complex

Abstract

The dinuclear RuII arene complexes [{(eta6-arene)RuCl}2(mu-2,3-dpp)](PF6)2, arene=indan (1), benzene (2), p-cymene (3), or hexamethylbenzene (4) and 2,3-dpp=2,3-bis(2-pyridyl)pyrazine, have been synthesized and characterized. Upon irradiation with UVA light, complexes 1 and 2 readily underwent arene loss, while complexes 3 and 4 did not. The photochemistry of 1 was studied in detail. In the X-ray structure of [{(eta6-indan)RuCl}2(mu-2,3-dpp)](PF6)2 (1), 2,3-dpp bridges two RuII centers 6.8529(6) A apart. In water, aquation of 1 in the dark occurs with replacement of chloride with biexponential kinetics and decay constants of 100+/-1 min-1 and 580+/-11 min-1. This aquation was suppressed by 0.1 M NaCl. UV or visible irradiation of 1 in aqueous or methanolic solution led to arene loss. The fluorescence of the unbound arene is approximately 40 times greater than when it is complexed. Irradiation of 1 also had a significant effect on its interactions with DNA. The DNA binding of 1 is increased after irradiation. The non-irradiated form of 1 preferentially formed DNA adducts that only weakly blocked RNA polymerase, while irradiation of 1 transformed the adducts into stronger blocks for RNA polymerase. The efficiency of irradiated 1 to form DNA interstrand cross-links was slightly greater than that of cisplatin in both 10 mM NaClO4 and 0.1 M NaCl. In contrast, the interstrand cross-linking efficiency of non-irradiated 1 in 10 mM NaClO4 was relatively low. An intermediate amount of cross-linking was observed when the sample of DNA already modified by non-irradiated 1 was irradiated. DNA unwinding measurements supported the conclusion that both mono- and bifunctional adducts with DNA can form. These results show that photoactivation of dinuclear RuII arene complexes can simultaneously produce a highly reactive ruthenium species that can bind to DNA and a fluorescent marker (the free arene). Importantly, the mechanism of photoreactivity is also independent of oxygen. These complexes, therefore, have the potential to combine both photoinduced cell death and fluorescence imaging of the location and efficiency of the photoactivation process.

Ruthenium(II)-arene complexes with naphthalimide-tagged N,O- and N,N-chelating ligands: Synthesis and biological evaluation

“…While the exact mode of action of the cytotoxic ruthenium(II)-arene complexes is not clearly understood yet, DNA is considered to be one of their potential biological targets [51][52][53][54][55]. Hence, to evaluate the mode of interactions of the new ruthenium(II)-cymene complexes explored in the present study with DNA, UV-vis absorption and fluorescence spectroscopy, and gels electrophoresis studies were carried out.…”

Photoactivatable Organometallic Pyridyl Ruthenium(II) Arene Complexes

“…7 A few dinuclear complexes based on the typical half-sandwich motif have been also studied. Amongst them, the complex [{(η 6 -ind)Ru(Cl)} 2 (μ-2,3-dpp) 2 ] 2+ where dpp is 2,3-bis(2-pyridyl)pyrazine 8 releases the arene upon irradiation generating vacant coordination sites that make it more reactive towards DNA binding.…”

“…Studies of CT-DNA interactions in cell-free media suggest combined weak monofunctional coordinative and intercalative binding modes. The Ru II arene complexes [(η 6 -p-cym)Ru(bpm)(Py)] 2+ (1), [(η 6 -p-cym)Ru(bpm)(4-MeOPy)] 2+ (3), [(η 6 -p-cym)Ru(4,4'-biPy)] 2+ (4), [(η 6 -hmb)Ru(bpm)(Py)] 2+ (8), [(η 6 -ind)Ru(bpm)(Py)] 2+ (9), [(η 6 -p-cym)Ru(phen)(Py)] 2+ (10),…”

Photo-Induced Pyridine Substitution in cis-[Ru(bpy)2(py)2]Cl2: A Snapshot by Time-Resolved X-ray Solution Scattering

“…4,[13][14][15][16][17][18] Obtaining structural information on transient species generated by light excitation is therefore crucial to the field of photoactivatable metal-based anticancer agents. It can reveal the mechanism of activation of the 'prodrug' helping to understand the overall mechanism of action of the metal complex in cells.…”