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, [(η 6 - p -cymene)RuCl{κ 2 N -(HCNR) 2 }]NO 3 (R = Cy, [ 1 ]NO 3; R = 4-C 6 H 10 OH, [ 2 ]NO 3; R = 4-C 6 H 4 OH, [ 3 ]NO 3 ), were prepared in near-quantitative yields as their nitrate salts. [ 2 ]NO 3 displays high water solubility. The potential of the α-diimine ligand in [ 3 ]NO 3 as a carrier of bioactive molecules was investigated via esterification reactions with the hydroxyl groups. Thus, the double-functionalized derivatives [(η 6 - p -cymene)RuCl{κ 2 N -(HCN(4-C 6 H 4 OCO-R)) 2 }]NO 3 (R = aspirinate, [ 5 ]NO 3; valproate, [ 6 ]NO 3 ) 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 ]NO 3 . 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 IC 50 values in the low micromolar range. The complexes functionalized with bioactive components, i.e., [ 5 ]NO 3 and [ 6 ]NO 3, exhibited a marked increase in the cytotoxicity with respect to the precursor [ 3 ]NO 3 .