Sterically demanding methoxy and methyl groups in ruthenium complexes lead to enhanced quantum yields for blue light triggered photodissociation

Ruthenium complexes containing a sterically congested metal center can serve as light activated prodrugs through photo-activated chemotherapy (PACT). In this work, we modified PACT agents containing 6,6′-dihydroxybipyridine (6,6′-dhbp) (Papish et al. , Inorg. Chem. , 2017, 56 , 7519) by replacing it with a sterically bulky isoelectronic ligand, 6,6′-dimethoxybipyridine (6,6′-dmbp). The resulting complexes, [(phen) 2 Ru(6,6′-dmbp)]Cl 2 ( 2 OMe , phen = 1,10-phenanthroline) and [(dop) 2 Ru(6,6′-dmbp)]Cl 2 ( 3 OMe , dop = 2,3-dihydro-[1,4]dioxino[2,3- f ][1,10]phenanthroline), have been fully characterized and display enhanced quantum yields for blue light triggered photodissociation of 0.024(6) and 0.0030(2), respectively. We have also synthesized 4 OH = [(dmphen) 2 Ru(4,4′-dhbp)]Cl 2 wherein dmphen = 2,9-dimethyl-1,10-phenanthroline and 4,4′-dhbp = 4,4′-dihydroxybipyridine. These ligands enhance steric bulk near the metal center and move the hydroxy groups further from the metal center, respectively. Complex 4 OH displays a relatively low quantum yield of 0.0014(2). All of the new complexes ( 2 OMe , 3 OMe , 4 OH ) were tested in breast cancer cells (MDA-MB-231) and were non-toxic (IC 50 > 100 μM). This has been interpreted in terms of unfavorable log( D o/w ) values and furthermore photodissociation alone is insufficient for cytotoxicity. We also report the crystal structures of 4 OH and 2 OMe , the thermodynamic acidity of complex 4 OH , and the redox potentials for all new complexes. Ruthenium complexes exhibit enhanced photodissociation quantum yields due to bulky, weak donor ligands, illustrating the impact of electronics and sterics.