Photocytotoxicity and photoinduced phosphine ligand exchange in a Ru(ii) polypyridyl complex

Abstract

Two new tris-heteroleptic Ru(ii) complexes with triphenylphosphine (PPh₃) coordination, cis-[Ru(phen)₂(PPh₃)(CH₃CN)]²⁺ (1a, phen = 1,10-phenanthroline) and cis-[Ru(biq)(phen)(PPh₃)(CH₃CN)]²⁺ (2a, biq = 2,2'-biquinoline), were synthesized and characterized for photochemotherapeutic applications. Upon absorption of visible light, 1a exchanges a CH₃CN ligand for a solvent water molecule. Surprisingly, the steady-state irradiation of 2a followed by electronic absorption and NMR spectroscopies reveals the photosubstitution of the PPh₃ ligand. Phosphine photoinduced ligand exchange with visible light from a Ru(ii) polypyridyl complex has not previously been reported, and calculations reveal that it results from a trans-type influence in the excited state. Complexes 1a and 2a are not toxic against the triple negative breast cancer cell line MDA-MB-231 in the dark, but upon irradiation with blue light, the activity of both complexes increases by factors of >4.2 and 5.8, respectively. Experiments with PPh₃ alone show that the phototoxicity observed for 2a does not arise from the released phosphine ligand, indicating the role of the photochemically generated ruthenium aqua complex on the biological activity. These complexes represent a new design motif for the selective release of PPh₃ and CH₃CN for use in photochemotherapy.

Fig. 1. Schematic representation of the molecular structures of 1a, 1b, 2a, and 2b.

Fig. 2. Electronic absorption spectra of 1a (solid blue), 1b (dashed blue), 2a (solid red), and 2b (dashed red) in CH₃CN.

Fig. 3. Changes following the irradiation of 1a (λ_irr ≥ 395 nm) to the (a) electronic absorption spectrum in H₂O, t_irr = 0–30 min, and (b) ¹H NMR spectrum in CD₃CN, t_irr = 0, 4, and 14 min.

Fig. 4. (a) Changes in the electronic absorption spectrum of 2a in CH₃CN following irradiation, t_irr = 0–5 min and (b) electronic absorption spectra of 2a before irradiation (solid red), following 30 min irradiation (dashed red), and 2b (black).

Fig. 5. Changes in the (a) ¹H and (b) ³¹P{H} NMR spectra of 2a in CD₃CN at t_irr = 0, 4, and 15 min (λ_irr ≥ 395 nm).

Fig. 6. Changes following irradiation (λ_irr ≥ 395 nm) in the electronic absorption spectrum of 2a in pyridine from (a) t_irr = 0–2.5 min and (b) t_irr = 3.5–20 min.

Fig. 7. Time dependent concentrations of 2a (red circles), cis-[Ru(biq)(phen)(py)(CH₃CN)]²⁺ (I, black circles), and cis-[Ru(biq)(phen)(py)₂]²⁺ following irradiation (λ_irr ≥ 395 nm) in pyridine from t = 0 to t = 1200 s. The dashed lines are least-squares fits to a consecutive reaction model with a system of equations describing the time-dependent concentration of each compound (see text).

Fig. 8. ORTEP plots of 1a, 2a, and 2b (thermal ellipsoids have been drawn at 50% probability and hydrogen atoms, PF₆⁻ molecules, and co-crystallized solvent molecules have been omitted for clarity); Ru: cyan, N: light purple, C: grey, and P: magenta.

Fig. 9. Mulliken spin densities (MSDs) on ruthenium and the summed densities on each ligand in the calculated lowest energy triplet excited states of 1a and 2a.