Ruthenium Complexes with Protic Ligands: Influence of the Position of OH Groups and π Expansion on Luminescence and Photocytotoxicity.

Protic ruthenium complexes using the dihydroxybipyridine (dhbp) ligand combined with a spectator ligand (N,N = bpy, phen, dop, Bphen) have been studied for their potential activity vs. cancer cells and their photophysical luminescent properties. These complexes vary in the extent of π expansion and the use of proximal (6,6'-dhbp) or distal (4,4'-dhbp) hydroxy groups. Eight complexes are studied herein as the acidic (OH bearing) form, [(N,N)2Ru(n,n'-dhbp)]Cl2, or as the doubly deprotonated (O- bearing) form. Thus, the presence of these two protonation states gives 16 complexes that have been isolated and studied. Complex 7A, [(dop)2Ru(4,4'-dhbp)]Cl2, has been recently synthesized and characterized spectroscopically and by X-ray crystallography. The deprotonated forms of three complexes are also reported herein for the first time. The other complexes studied have been synthesized previously. Three complexes are light-activated and exhibit photocytotoxicity. The log(Do/w) values of the complexes are used herein to correlate photocytotoxicity with improved cellular uptake. For Ru complexes 1-4 bearing the 6,6'-dhbp ligand, photoluminescence studies (all in deaerated acetonitrile) have revealed that steric strain leads to photodissociation which tends to reduce photoluminescent lifetimes and quantum yields in both protonation states. For Ru complexes 5-8 bearing the 4,4'-dhbp ligand, the deprotonated Ru complexes (5B-8B) have low photoluminescent lifetimes and quantum yields due to quenching that is proposed to involve the 3LLCT excited state and charge transfer from the [O2-bpy]2- ligand to the N,N spectator ligand. The protonated OH bearing 4,4'-dhbp Ru complexes (5A-8A) have long luminescence lifetimes which increase with increasing π expansion on the N,N spectator ligand. The Bphen complex, 8A, has the longest lifetime of the series at 3.45 µs and a photoluminescence quantum yield of 18.7%. This Ru complex also exhibits the best photocytotoxicity of the series. A long luminescence lifetime is correlated with greater singlet oxygen quantum yields because the triplet excited state is presumably long-lived enough to interact with 3O2 to yield 1O2.

Factors that influence singlet oxygen formation vs. ligand substitution for light-activated ruthenium anticancer compounds.

This review focuses on light-activated ruthenium anticancer compounds and the factors that influence which pathway is favored. Photodynamic therapy (PDT) is favored by π expansion and the presence of low-lying triplet excited states (e.g. 3MLCT, 3IL). Photoactivated chemotherapy (PACT) refers to light-driven ligand dissociation to give a toxic metal complex or a toxic ligand upon photo substitution. This process is driven by steric bulk near the metal center and weak metal-ligand bonds to create a low-energy 3MC state with antibonding character. With protic dihydroxybipyridine ligands, ligand charge can play a key role in these processes, with a more electron-rich deprotonated ligand favoring PDT and an electron-poor protonated ligand favoring PACT in several cases.

Light-responsive and Protic Ruthenium Compounds Bearing Bathophenanthroline and Dihydroxybipyridine Ligands Achieve Nanomolar Toxicity towards Breast Cancer Cells.

We report new ruthenium complexes bearing the lipophilic bathophenanthroline (BPhen) ligand and dihydroxybipyridine (dhbp) ligands which differ in the placement of the OH groups ([(BPhen)2 Ru(n,n'-dhbp)]Cl2 with n = 6 and 4 in 1A and 2A , respectively). Full characterization data are reported for 1A and 2A and single crystal X-ray diffraction for 1A . Both 1A and 2A are diprotic acids. We have studied 1A , 1B , 2A , and 2B (B = deprotonated forms) by UV-vis spectroscopy and 1 photodissociates, but 2 is light stable. Luminescence studies reveal that the basic forms have lower energy 3 MLCT states relative to the acidic forms. Complexes 1A and 2A produce singlet oxygen with quantum yields of 0.05 and 0.68, respectively, in acetonitrile. Complexes 1 and 2 are both photocytotoxic toward breast cancer cells, with complex 2 showing EC50 light values as low as 0.50 µM with PI values as high as >200 vs. MCF7. Computational studies were used to predict the energies of the 3 MLCT and 3 MC states. An inaccessible 3 MC state for 2B suggests a rationale for why photodissociation does not occur with the 4,4'-dhbp ligand. Low dark toxicity combined with an accessible 3 MLCT state for 1 O2 generation explains the excellent photocytotoxicity of 2.