Tuning the cytotoxic properties of new ruthenium(III) and ruthenium(II) complexes with a modified bis(arylimino)pyridine Schiff base ligand using bidentate pyridine-based ligands: Topical issue in honor of Ivano Bertini. Guest editors Lucia Banci, Claudio Luchinat

Synthesis, spectroscopy, characterization, structures, and cytotoxicity studies of 2,6-bis(2,6-diisopropylphenyliminomethyl)pyridine (LLL) ruthenium compounds are described. The starting compound [RuCl₃(LLL)] has been fully characterized using IR spectroscopy, UV-vis spectroscopy, electrospray ionization mass spectrometry, and NMR spectroscopy. In addition, the crystal structure of the ligand LLL has been determined using single-crystal X-ray diffraction. With the ruthenium(III) trichloride compound as starting material, a new family of Ru(II) complexes with a number of neutral and charged bidentate co-ligands have been synthesized and used for characterization and cytotoxicity studies. The synthesis of the corresponding [Ru^IILLL(LL)Cl] ^+/0 complexes with co-ligands - LL is 1,10-phenanthroline, 2,2a'-bipyridyl, 2-(phenylazo)pyridine, 2-(phenylazo)-3-methylpyridine, 2-(tolylazo)pyridine, or the anionic 2-picolinate - is reported. Analytical, spectroscopic (IR spectroscopy, UV-vis spectroscopy, ¹H NMR spectroscopy, and electrospray ionization mass spectrometry), and structural characterization of the new compounds is described. Crystal structure analyses of two Ru(II) compounds show a slightly distorted octahedral Ru(II) geometry with tridentate LLL coordinated in a planar meridional fashion, and the chelating co-ligand (LL) and a chloride ion complete the octahedron. The co-ligand plays a significant role in modulating the physicochemical and cytotoxic properties of these new ruthenium complexes. The in vitro cytotoxicity of these new Ru(II) complexes (half-maximal inhibitory concentration, IC ₅₀, of 0.5-1.5 μM), in comparison with the parent Ru(III) compound (half-maximal inhibitory concentration of 3.9-4.3 μM) is higher for several of the human cancer cell lines tested. The cytotoxic activity of some of the new ruthenium compounds is even higher than that of cisplatin in the same cancer cell lines. The cytotoxicity of these new anticancer compounds is discussed in the light of structure-based activity relationships, and a possible mechanism of action is suggested. Graphical abstract: Synthesis, spectroscopy, structures, and cytotoxicity studies of new Ru(III) and Ru(II) compounds with a substituted bis(arylimino)pyridine ligand and bidentate co-ligands are reported. The co-ligands play a significant role in modulating the physicochemical and cytotoxic properties. The in vitro cytotoxicity data are discussed in the light of structure-based activity relationships (SARs). Highlights: (a) The synthesis, structure, and spectroscopic characterization of 2,6-bis(2,6- diisopropylphenyliminomethyl)pyridine, a tridentate Schiff base ligand, are reported. (b) A new Ru(III) complex with a bis(arylimino)pyridine Schiff base ligand has been synthesized and characterized spectroscopically. (c) A family of Ru(II) compounds with a bis(arylimino)pyridine Schiff base ligand as a primary ligand and bidentate pyridine-based co-ligands are reported. (d) The cytotoxic activity of Ru(II) and Ru(III) compounds has been studied systematically. [Figure not available: see fulltext.]