Acylhydrazone-based ferrocene-iridium(III) heteronuclear metal complexes: In vivo/in vitro anticancer evaluation...

Iridium(III) complexes and ferrocenyl derivatives have recently emerged as promising alternatives to platinum-based anticancer agents, owing to their distinctive anticancer mechanisms. This study presented the creation of six acylhydrazone-based ferrocene‑iridium(III) heteronuclear complexes, each featuring polymetallic core, despite the inherent challenges in the design and synthesis of polynuclear metal complexes. Among these, IrFP6, which integrating two iridium(III) centers with a ferrocene unit, demonstrated superior bioactivity, surpassing that of cisplatin, and showing efficacy against A549 lung cancer cells and cisplatin-resistant A549/DDP cells. IrFP6 showed the multifaceted mechanism of action including the accumulation in mitochondria and the arrest of cell cycle at S phase, a reduction of mitochondrial membrane potential and an accumulation of intracellular reactive oxygen species, resulting in A549 cell apoptosis. The nude mouse model experiments further confirmed that IrFP6 exhibited superior in vivo antitumor activity and safety in comparison to cisplatin. This work thus provides an original structural model for the design of non‑platinum multi-core metal anticancer drugs.