Anticancer Cyclometalated Iridium(III) Complexes with Planar Ligands: Mitochondrial DNA Damage and Metabolism Disturbance

Emerging
studies have shown that mitochondrial DNA (mtDNA) is a
potential target for cancer therapy. Herein, six cyclometalated Ir­(III)
complexes Ir1–Ir6 containing a series of extended
planar diimine ligands have been designed and assessed for their efficacy
as anticancer agents. Ir1–Ir6 show much higher
cytotoxicity than cisplatin and they can effectively localize to mitochondria.
Among them, complexes Ir3 and Ir4 with dipyrido­[3,2-a:2′,3′-c]­phenazine (dppz)
ligands can bind to DNA tightly in vitro, intercalate
to mtDNA in situ, and induce mtDNA damage. Ir3- and Ir4-impaired mitochondria exhibit decline
of mitochondrial membrane potential, disability of adenosine
triphosphate generation, disruption of mitochondrial energetic and
metabolic status, which subsequently cause protective mitophagy, G0/G1 phase cell cycle arrest, and apoptosis. In
vivo antitumor evaluations also show that Ir4 can inhibit
tumor xenograft growth effectively. Overall, our work proves that
targeting the mitochondrial genome may present an effective strategy
to develop metal-based anticancer agents to overcome cisplatin resistance.