Organometallic Ru(II) Photosensitizers Derived from π‑Expansive Cyclometalating Ligands: Surprising Theranostic PDT Effects

The purpose of the present study was to investigate the influence of π-expansive cyclometalating ligands on the photophysical and photobiological properties of organometallic Ru­(II) compounds. Four compounds with increasing π conjugation on the cyclometalating ligand were prepared, and their structures were confirmed by HPLC, 1D and 2D ¹H NMR, and mass spectrometry. The properties of these compounds differed substantially from their Ru­(II) polypyridyl counterparts. Namely, they were characterized by red-shifted absorption, very weak to no room temperature phosphorescence, extremely short phosphorescence state lifetimes (<10 ns), low singlet oxygen quantum yields (0.5–8%), and efficient ligand-centered fluorescence. Three of the metal complexes were very cytotoxic to cancer cells in the dark (EC₅₀ values = 1–2 μM), in agreement with what has traditionally been observed for Ru­(II) compounds derived from small C^N ligands. Surprisingly, the complex derived from the most π-expansive cyclometalating ligand exhibited no cytotoxicity in the dark (EC₅₀ > 300 μM) but was phototoxic to cells in the nanomolar regime. Exceptionally large phototherapeutic margins, exceeding 3 orders of magnitude in some cases, were accompanied by bright ligand-centered intracellular fluorescence in cancer cells. Thus, Ru­(II) organometallic systems derived from π-expansive cyclometalating ligands, such 4,9,16-triazadibenzo­[a,c]­napthacene (pbpn), represent the first class of potent light-responsive Ru­(II) cyclometalating agents with theranostic potential.