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

Abstract

A series of five ruthenium complexes containing triphenyl phosphine groups known to enhance both cellular penetration and photoinduced ligand exchange, <i>cis</i>-[Ru(bpy)₂(P(<i>p</i>-R-Ph)₃)(CH₃CN)]²⁺, where bpy = 2,2'-bipyridine and P(<i>p</i>-R-Ph)₃ represent <i>para</i>-substituted triphenylphosphine ligands with R = -OCH₃ (<b>1</b>), -CH₃ (<b>2</b>) -H (<b>3</b>), -F (<b>4</b>), and -CF₃ (<b>5</b>), were synthesized and characterized. The photolysis of <b>1-5</b> in water with visible light (<i>λ</i> _irr ≥ 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, <i>Φ</i> ₄₀₀, where <b>1</b> is the most efficient with a <i>Φ</i> ₄₀₀ = 0.076(2), and <b>5</b> the least photoactive complex, with <i>Φ</i> ₄₀₀ = 0.026(2). This trend is unexpected based on the red-shifted metal-to-ligand charge transfer (MLCT) absorption of <b>1</b> as compared to that of <b>5</b>, but can be correlated to the substituent Hammett <i>para</i> parameters and p<i>K</i> _a values of the ancillary phosphine ligands. Complexes <b>1-5</b> are not toxic towards the triple negative breast cancer cell line MDA-MB-231 in the dark, but <b>3</b> and <b>5</b> are >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 by <b>5</b> upon irradiation. These findings provide a foundation for understanding the role of phosphine ligands on photoinduced ligand substitution and show the enhancement afforded by -CF₃ groups on photochemotherapy, which will aid the future design of photocages for photochemotherapeutic drug delivery.