High cytotoxic and apoptotic effects of platinum(ii) complexes bearing the 4-acridinol ligand

Abstract

Here, two platinum(II) complexes, namely [Pt^II(Q)(DMSO)Cl] (PtQ) and [Pt^II(A)(DMSO)Cl] (PtA), bearing 8-hydroxyquinoline (HQ) and 4-acridinol (HA) ligands were synthesized for the first time and fully characterized by elemental analysis, NMR and IR spectroscopies, and X-ray crystallography. The two 4-acridinol Pt complexes (PtQ and PtA) were active against cisplatin-resistant SK-OV-3/DDP cancer cells with lower IC₅₀ values than cisplatin. Notably, complex PtA exhibited IC₅₀ values (0.05 ± 0.02 μM) that were an order of two and three magnitude lower than those of the 8-hydroxyquinoline Pt complex PtQ (5.08 ± 0.47 μM) and clinical cisplatin (71.23 ± 1.02 μM), respectively. Interestingly, complex PtA displayed potent cytotoxic activity particularly in cisplatin-resistant SK-OV-3/DDP cells, but it was practically inactive against the human liver HL-7702 normal cells. Analyzing the uptake and distribution of complex PtA in the cisplatin-resistant SK-OV-3/DDP cells revealed that PtA was mainly localized in the mitochondria. In addition, complex PtA significantly caused the loss of bcl-2 and mitochondrial membrane potential (ΔΨ_m), increase in [Ca²⁺] and the reactive oxygen species (ROS) levels, cytochrome C (cyto C), apaf-1, and caspase-3/9 ratio in cisplatin-resistant SK-OV-3/DDP cells. Complex PtA may trigger cell apoptosis via a mitochondrial dysfunction pathway, whereas 8-hydroxyquinoline Pt complex PtQ does not. The better cytotoxicity and the more significant anticancer mechanism of complex PtA than 8-hydroxyquinoline Pt complex PtQ should be undoubtedly correlated with the key roles of the more extended planar 4-acridinol (HA) ligand.