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

摘要

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]PF_(6), 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 p -cymene ( p -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 [(η~(6)- p -cym)Ru(P^P)Cl]PF_(6) ( 5 ) 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 [(η~(5)-Cp*)Ir(P^P)Cl]PF_(6) ( 1 ), ruthenium complex ( 5 ) 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 1 , 5 , and ligand BINAP were evaluated by cyclic voltammetry. Complexes 1 and 5 arrest cell cycles at the S phase, Sub-G_(1) phase and G_(1) phase, respectively, and cause cell apoptosis toward A549 cells.