α-Diimines as Versatile, Derivatizable Ligands in Ruthenium(II) <i>p</i>-Cymene Anticancer Complexes

Abstract

α-Diimines are among the most robust and versatile ligands available in synthetic coordination chemistry, possessing finely tunable steric and electronic properties. A series of novel cationic ruthenium(II) p-cymene complexes bearing simple α-diimine ligands, [(η⁶- p-cymene)RuCl{κ² N-(HCNR)₂}]NO₃ (R = Cy, [1]NO₃; R = 4-C₆H₁₀OH, [2]NO₃; R = 4-C₆H₄OH, [3]NO₃), were prepared in near-quantitative yields as their nitrate salts. [2]NO₃ displays high water solubility. The potential of the α-diimine ligand in [3]NO₃ as a carrier of bioactive molecules was investigated via esterification reactions with the hydroxyl groups. Thus, the double-functionalized derivatives [(η⁶- p-cymene)RuCl{κ² N-(HCN(4-C₆H₄OCO-R))₂}]NO₃ (R = aspirinate, [5]NO₃; valproate, [6]NO₃) and also [4]Cl (R = Me) were obtained in good-to-high yields. UV-vis and multinuclear NMR spectroscopy and cyclic voltammetric studies in aqueous solution revealed only minor ruthenium chloride hydrolytic cleavage, biologically accessible reduction potentials, and pH-dependent behavior of [3]NO₃. Density functional theory analysis was performed in order to compare the Ru-Cl bond strength in [1]⁺ with the analogous ethylenediamine complex, showing that the higher stability observed in the former is related to the electron-withdrawing properties of the α-diimine ligand. In vitro cytotoxicity studies were performed against tumorigenic (A2780 and A2780cisR) and nontumorigenic (HEK-293) cell lines, with the complexes bearing simple α-diimine ligands ranging from inactive to IC₅₀ values in the low micromolar range. The complexes functionalized with bioactive components, i.e., [5]NO₃ and [6]NO₃, exhibited a marked increase in the cytotoxicity with respect to the precursor [3]NO₃.