Trifluoromethyl substitution enhances photoinduced activity against breast cancer cells but reduces ligand exchange in Ru(ii) complex

Abstract

A series of five ruthenium complexes containing triphenyl phosphine groups known to enhance both cellular penetration and photoinduced ligand exchange,cis-[Ru(bpy)2(P(p-R-Ph)3)(CH3CN)]2+, where bpy = 2,2′-bipyridine and P(p-R-Ph)3representpara-substituted triphenylphosphine ligands with R = -OCH3(1), -CH3(2) -H (3), -F (4), and -CF3(5), were synthesized and characterized. The photolysis of1-5in water with visible light (λirr≥ 395 nm) results in the substitution of the coordinated acetonitrile with a solvent molecule, generating the corresponding aqua complex as the single photoproduct. A 3-fold variation in quantum yield was measured with 400 nm irradiation,Φ400, where1is the most efficient with aΦ400= 0.076(2), and5the least photoactive complex, withΦ400= 0.026(2). This trend is unexpected based on the red-shifted metal-to-ligand charge transfer (MLCT) absorption of1as compared to that of5, but can be correlated to the substituent Hammettparaparameters and pKavalues of the ancillary phosphine ligands. Complexes1-5are not toxic towards the triple negative breast cancer cell line MDA-MB-231 in the dark, but3and5are >4.2 and >19-fold more cytotoxic upon irradiation with blue light, respectively. A number of experiments point to apoptosis, and not to necrosis or necroptosis, as the mechanism of cell death by5upon irradiation. These findings provide a foundation for understanding the role of phosphine ligands on photoinduced ligand substitution and show the enhancement afforded by -CF3groups on photochemotherapy, which will aid the future design of photocages for photochemotherapeutic drug delivery.