Half-Sandwich Iridium(III) and Ruthenium(II) Complexes Containing P^P-Chelating Ligands: A New Class of Potent Anticancer Agents with Unusual Redox Features

A series of half-sandwich Ir^III pentamethylcyclopentadienyl and Ru^II arene complexes containing P^P-chelating ligands of the type [(Cp^x/arene)­M­(P^P)­Cl]­PF₆, where M = Ir, Cp^x is pentamethylcyclopentadienyl (Cp*), or 1-biphenyl-2,3,4,5-tetramethyl cyclopentadienyl (Cp^xbiPh); M = Ru, arene is 3-phenylpropan-1-ol (bz-PA), 4-phenylbutan-1-ol (bz-BA), or <i>p</i>-cymene (<i>p</i>-cym), and P^P is 2,20-bis­(diphenylphosphino)-1,10-binaphthyl (BINAP), have been synthesized and fully characterized, three of them by X-ray crystallography, and their potential as anticancer agents explored. All five complexes showed potent anticancer activity toward HeLa and A549 cancer cells. The introduction of a biphenyl substituent on the Cp* ring for the iridium complexes has no effect on the antiproliferative potency. Ruthenium complex [(η⁶-<i>p</i>-cym)­Ru­(P^P)­Cl]­PF₆ (<b>5</b>) displayed the highest potency, about 15 and 7.5 times more active than the clinically used cisplatin against A549 and HeLa cells, respectively. No binding to 9-MeA and 9-EtG nucleobases was observed. Although these types of complexes interact with ctDNA, DNA appears not to be the major target. Compared to iridium complex [(η⁵-Cp*)­Ir­(P^P)­Cl]­PF₆ (<b>1</b>), ruthenium complex (<b>5</b>) showed stronger ability to interfere with coenzyme NAD⁺/NADH couple through transfer hydrogenation reactions and to induce ROS in cells, which is consistent with their anticancer activities. The redox properties of the complexes <b>1</b>, <b>5</b>, and ligand BINAP were evaluated by cyclic voltammetry. Complexes <b>1</b> and <b>5</b> arrest cell cycles at the S phase, Sub-G₁ phase and G₁ phase, respectively, and cause cell apoptosis toward A549 cells