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

Abstract

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)₂Ru(6,6′-dmbp)]Cl₂ (2^OMe, phen = 1,10-phenanthroline) and [(dop)₂Ru(6,6′-dmbp)]Cl₂ (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)₂Ru(4,4′-dhbp)]Cl₂ 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 (IC₅₀ > 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.