Influence of the Steric Bulk and Solvent on the Photoreactivity of Ruthenium Polypyridyl Complexes Coordinated to l-Proline

Abstract

Ruthenium polypyridyl complexes are good candidates for photoactivated chemotherapy (PACT) provided that they are stable in the dark but efficiently photosubstitute one of their ligands. Here the use of the natural amino acid l-proline as a protecting ligand for ruthenium-based PACT compounds is investigated in the series of complexes Λ-[Ru(bpy)2(l-prol)]PF6 ([1a]PF6; bpy = 2,2′-bipyridine and l-prol = l-proline), Λ-[Ru(bpy)(dmbpy)(l-prol)]PF6 ([2a]PF6 and [2b]PF6; dmbpy = 6,6′-dimethyl-2,2′-bipyridine), and Λ-[Ru(dmbpy)2(l-prol)]PF6 ([3a]PF6). The synthesis of the tris-heteroleptic complex bearing the dissymmetric proline ligand yielded only two of the four possible regioisomers, called [2a]PF6 and [2b]PF6. Both isomers were isolated and characterized by a combination of spectroscopy and density functional theory calculations. The photoreactivity of all four complexes [1a]PF6, [2a]PF6, [2b]PF6, and [3a]PF6 was studied in water (H2O) and acetonitrile (MeCN) using UV–vis spectroscopy, circular dichroism spectroscopy, mass spectrometry, and 1H NMR spectroscopy. In H2O, upon visible-light irradiation in the presence of oxygen, no photosubstitution took place, but the amine of complex [1a]PF6 was photooxidized to an imine. Contrary to expectations, enhancing the steric strain by the addition of two ([2b]PF6) or four ([3a]PF6) methyl substituents did not lead, in phosphate-buffered saline (PBS), to ligand photosubstitution. However, it prevented photoxidation, probably as a consequence of the electron-donating effect of the methyl substituents. In addition, whereas [2b]PF6 was photostable in PBS, [2a]PF6 quantitatively isomerized to [2b]PF6 upon light irradiation. In pure MeCN, [2a]PF6 and [3a]PF6 showed non-selective photosubstitution of both the l-proline and dmbpy ligands, whereas the non-strained complex [1a]PF6 was photostable. Finally, in H2O–MeCN mixtures, [3a]PF6 showed selective photosubstitution of l-proline, thus demonstrating the active role played by the solvent on the photoreactivity of this series of complexes. The role of the solvent polarity and coordination properties on the photochemical properties of polypyridyl complexes is discussed.

Ruthenium-based PACT compounds based on an N,S non-toxic ligand: a delicate balance between photoactivation and thermal stability

“…In addition to these two new species, the signals of free dmbpy (7.86, 7.74, and 7.37 ppm) and free mtpa (singlet at 2.10 ppm) were also found, thus confirming the competing photosubstitution of both dmbpy and mtpa. Although parallel photosubstitution of two distinct ligands has not been described very often, it has been observed recently in our group in a similar complex, [Ru(bpy)(dmbpy)(L-proline)]PF 6 [13].…”

“…All reactants and solvents were used without further purification. [13,23]. Sephadex LH-20 was used for the Size Exclusion Column (SEC) chromatography.…”

“…1H, N ax ), 3.14 -3.01 (m, 2H, N eq + γ ax ), 2.92 (s, 3H, AMe), 2.67 -2.57 (m, 1H, α), 2.53 -2.43 (m, 1H, γ eq ), 2.17 -2.07 (m, 1H, α), 2.06 -1.97 (m, 1H, β), 1.96 -1.87 (m, 1H, β), 1.62 (s, 3H, BMe), 1.58 (s, 3H, MeS-). 13 Table 3 for the details). Then, 600 µL of the stock solution were transferred, under N 2 , into a NMR tube.…”

Photolabile Ru Model Complexes with Chelating Diimine Ligands for Light‐Triggered Drug Release

“…Although parallel photorelease of two different ligands has not been often described, it has been observed recently in the complex [Ru(bpy)(dmbpy)(L‐proline)][PF 6 ], in which substitution of both dmbpy and l ‐proline occurred upon illumination …”

Selective Preparation of a Heteroleptic Cyclometallated Ruthenium Complex Capable of Undergoing Photosubstitution of a Bidentate Ligand

“…Thermal stability is an important feature of photoactivatable prodrugs, and the stabilityi nt he dark of all four complexes was studied in CH 3 CN by UV/Vis spectrophotometry. [33] Under air,s olutionso fc omplexes [3]PF 6 ,[ 4]PF 6 ,a nd [5]PF 6 in CH 3 CN did not show any significant changes in their UV/Vis spectra over 10 h, except for ag eneral increasei na bsorbance due to evaporation of the solvent ( Figure S5a-d). Thus, in CH 3 CN in the dark, neither oxidation nor thermal substitution of the N,S ligand by solventm olecules occurred.…”