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 p K 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 (IC 50 = 0.060 ± 0.016 μM) toward lung cancer cells, which was 7 times higher than that in the dark (IC 50 = 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 ( 1 O 2 ), and (3) induction of cell death occurs via the intrinsic pathway of apoptosis.