Naphthalene Diimide-Functionalized Half-Sandwich Ru(II) Complexes as Mitochondria-Targeted Anticancer and Antimetastatic Agents

In this work, four naphthalene diimide (NDI)-functionalized half-sandwich Ru(II) complexes <b>Ru1</b>–<b>Ru4</b> bearing the general formula [(η⁶-arene)Ru^II(N^N)Cl]PF₆, where arene = benzene (bn), <i>p</i>-cymene (<i>p</i>-cym), 1,3,5-trimethylbenzene (tmb), and hexamethylbenzene (hmb), have been synthesized and characterized. By introducing the NDI unit into the N,N-chelating ligand of these half-sandwich complexes, the poor luminescent half-sandwich complexes are endowed with excellent emission performance. Besides, modification on the arene ligand of arene-Ru(II) complexes can influence the electron density of the metal center, resulting in great changes in the kinetic properties, catalytic activities in the oxidative conversion of NADH to NAD⁺, and biological activities of these compounds. Particularly, <b>Ru4</b> exhibits the highest reactivity and the strongest inhibitory activity against the growth of three tested cancer cell lines. Further study revealed that <b>Ru4</b> can enter cells quickly in an energy-dependent manner and preferentially accumulate in the mitochondria of MDA-MB-231 cells, inducing cell apoptosis via reactive oxygen species overproduction and mitochondrial dysfunction. Significantly, <b>Ru4</b> can effectively inhibit the cell migration and invasion. Overall, the complexation with NDI and modification on the arene ligand endowed the half-sandwich Ru(II) complexes with improved spectroscopic properties and anticancer activities, highlighting their potential applications for cancer treatment.