Organoiridium(III) half-sandwich complexes have emerged as powerful contenders in the search for next-generation anticancer agents. Here we report on a series of [Ir(η5-Cpx)Cl(LNP)]PF6 cyclopentadienyl complexes innovatively incorporating N,P-donor phosphinoalkylamines (LNP).
The structural integrity and solution behavior of these compounds were assessed using e.g., multinuclear NMR, HPLC, and mass spectrometry, revealing exceptional stability under physiologically relevant conditions. These experiments were followed by evaluation of their anticancer potential in vitro on several cell lines in 2D and 3D systems, the potential mechanism of action were revealed, and anticancer effect on in vivo murine model was evaluated.
Performed chemico-physical analyses showed that the studied complexes are stable under the aqueous conditions and in the presence of relevant biomolecules. Cytotoxicity screening demonstrated that these complexes exhibit superior activity to cisplatin. Unlike cisplatin, which induces G2/M cell cycle arrest, our complexes predominantly halt the cell cycle at the G1/S checkpoint. Mechanistic investigations using proteomics unveiled a strikingly distinct mode of action compared to cisplatin. Obtained results pinpointed mitochondria and ribosomes as potential molecular targets, confirmed by observed disruption of mitochondrial membrane potential. Our compounds also exhibited potent anti-migratory effects, suppressing key pathways involved in cancer metastasis. In vivo validation in a murine tumor model confirmed efficacy of a Cp*-bearing derivative that significantly reduced necrosis and lowered the mitotic index in tumors - critical markers of therapeutic response.
This study establishes organoiridium(III) complexes with N,P-donor phosphinoalkylamines as a new frontier in anticancer drug design, with an unprecedented mechanism of action that diverges not only from traditional Pt-based DNA-targeting therapies but also from known non-platinum anticancer metallodrugs. Their unique molecular targeting and potent anticancer efficacy pave the way for their development as next-generation therapeutics.
Supported by the grant of the Ministry of Health of the Czech Republic (project NU22-08-00236).