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

Abstract

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.

Phosphorescent metal complexes as theranostic anticancer agents: combining imaging and therapy in a single molecule

“…7,12,16,35 Although a few reports have shown that these complexes can target the protein or DNA in cells, no denite SAR has been reported. 14,36,37 Iridium complexes are the most prominent ones among the metal complexes reported as theranostic anticancer agents. The cellular uptake of many drugs is usually related to their lipophilicity, while the dependence of cell penetration capabilities of iridium complexes on lipophilicity is not so obvious, and their cellular uptake mechanisms and intracellular transport pathways are largely unknown.…”

Mitocans Revisited: Mitochondrial Targeting as Efficient Anti-Cancer Therapy

“…It has been reported that cyclomethylated Ir(III) complexes can intercalate into mtDNA and induce mtDNA damage, followed by a decline of mitochondrial membrane potential, suppression of ATP generation, and disruption of mitochondrial energetics and metabolic status, eventually causing cancer cell apoptosis [102]. Additionally, using an mtDNA-depletion model, we found that DHODH-driven pyrimidine biosynthesis is an essential pathway which links respiration to tumorigenesis, demonstrating that DHODH could be a potential wide-spectrum target for cancer therapy [9].…”

Synthesis, Characterization, DNA/HSA Interactions, and Anticancer Activity of Two Novel Copper(II) Complexes with 4-Chloro-3-Nitrobenzoic Acid Ligand

“…Hence, novel non-Pt (II/IV) anticancer complexes with fewer side effects are urgently required [ 9 , 10 ]. Copper(II) complexes have attracted attention in medicinal inorganic chemistry research [ 11 , 12 , 13 , 14 , 15 , 16 ]. Copper(II) is an essential micronutrient and a structural and catalytic cofactor in numerous biochemical pathways.…”