New Ru(ii) complex for dual photochemotherapy: release of cathepsin K inhibitor and 1O2 production

Abstract

A new complex, [Ru(tpy)(dppn)(Cbz-Leu-NHCH₂CN)]²⁺ (1, tpy = 2,2′:6′,2′′-terpyridine, dppn = benzo[i]dipyrido[3,2-a:2′,3′-c]phenazine) was synthesized and its photochemical properties were investigated. This complex undergoes photorelease of the Cbz-Leu-NHCH₂CN ligand, a known cathepsin K inhibitor, with a quantum yield, Φ₄₅₀, of 0.0012(4) in water (λ_irr = 450 nm). In addition, 1 sensitizes the production of singlet oxygen upon visible light irradiation with quantum yield, Φ_Δ, of 0.64(3) in CH₃OH. The photophysical properties of 1 were compared with those of [Ru(tpy)(bpy)(Cbz-Leu-NHCH₂CN)]²⁺ (2, bpy = 2,2′-bipyridine), [Ru(tpy)(dppn)(CH₃CN)]²⁺ (3), and [Ru(tpy)(bpy)(CH₃CN)]²⁺ (4) to evaluate the effect of the release of the Cbz-Leu-NHCH₂CN inhibitor relative to the CH₃CN ligand, as well as the role of dppn as the bidentate ligand for ¹O₂ production instead of bpy. Nanosecond transient absorption spectroscopy confirms the formation of the long-lived dppn-centered ³ππ* state in 1 and 3 with a maximum at ∼540 nm and τ ∼20 μs in deaerated acetonitrile. Complexes 1 and 3 are able to cause photoinduced damage to DNA (λ_irr ≥ 395 nm), whereas 2 and 4 do not photocleave DNA under similar experimental conditions. These results suggest that 1 is a promising agent for dual activity, both releasing a drug and producing singlet oxygen, and is poised to exhibit enhanced biological activity in phototochemotherapy upon irradiation with visible light.