Ruthenium Pyrazole Complexes: A Family of Highly Active Metallodrugs for Photoactivated Chemotherapy

Ruthenium complexes bearing bis pyrazole (pzH) ligands, cis-[Ru(bpy)₂(R-pzH)₂]²⁺ (bpy = 2,2'-bipyridine, R = -H, -Cl), were examined as photoactivated anticancer prodrugs. A dicationic pyrazole complex deprotonated to give monocationic pyrazole-pyrazolate complexes, cis-[Ru(bpy)₂(R-pz^-)(R-pzH)]⁺, in an aqueous solution with pK_a values of 9.5 and 7.2 for R = H and R = Cl, respectively. Upon deprotonation, relative quantum yields of photosubstitution decreased while lipophilicity of the complexes increased according to the measurements of water-octanol coefficients. The ruthenium complex with 4-chloropyrazole ligands displayed high cytotoxicity upon light irradiation (IC₅₀ = 0.060 ± 0.016 μM) toward lung cancer cells, which was 7 times higher than that in the dark (IC₅₀ = 0.44 ± 0.07 μM). Additional experiments for the ruthenium R-pyrazole complexes indicated that (1) selective photodissociation of the 4-chloropyrazole ligand occurs from cis-[Ru(bpy)₂(4-Clpz^-)(4-ClpzH)]⁺, (2) photoinduced ligand dissociation is dominant rather than photoinduced generation of singlet oxygen (¹O₂), and (3) induction of cell death occurs via the intrinsic pathway of apoptosis.