Aims: This study aimed to evaluate the anticancer potential of half-sandwich (especially Rh(III) and Ir(III)) complexes featuring azo or Schiff bond ligands and to investigate their interactions with intracellular agents (NADH, GSH, ASA) and photoactivation as a potential mechanism for drug activation in tumor-like conditions.
Methods: A series of half-sandwich complexes incorporating various bidentate ligands were synthesized and characterized. Their antiproliferative activity was assessed in vitro. The reactivity of these complexes towards NADH, GSH, and ASA was investigated using spectroscopic techniques to monitor the reduction or cleavage of the azo or Schiff bonds and the potential release of terminal substituents. Irradiation of the complexes was also performed to explore their photoactivation properties and potential application in photodynamic therapy (PDT).
Results: The synthesized complexes demonstrated potent (low- or sub-micromolar) antiproliferative activity. Spectroscopic analysis revealed selective reactivity towards the tested intracellular reducing agents, with NADH, GSH, and ASA inducing the reduction or cleavage of the azo or Schiff bonds in several complexes [e.g., ref 1]. This biomolecule-induced transformation led to the release of terminal substituents in some cases. The stability of the complexes in aqueous solution was confirmed in the absence of biomolecules. The process was connected with the formation of reactive oxygen species (ROS). Irradiation of complexes also induced the formation of ROS and dramatically increased their antiproliferative activity (PI > 100).
Conclusion: The findings demonstrate that rationally-designed half-sandwich complexes with metal-activated ligands be activated by relevant intracellular biomolecules or by irradiation. The biomolecule- or light-triggered cleavage of the ligands, leading to the release of potentially bioactive substituents alongside the bioactive metal-based species, and to the ROS formation presents a novel strategy for the design of multi-component metallodrugs with potential for targeted cancer therapy.