α‑Diimines as Versatile, Derivatizable Ligands in Ruthenium(II) p‑Cymene Anticancer Complexes

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{κ2N-(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{κ2N-(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.