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 Ru1–Ru4 bearing the general formula [(η⁶-arene)Ru^II(N^N)Cl]PF₆, where arene = benzene (bn), p-cymene (p-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, Ru4 exhibits the highest reactivity and the strongest inhibitory activity against the growth of three tested cancer cell lines. Further study revealed that Ru4 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, Ru4 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.