Development of novel ruthenium(II)-arene complexes displaying potent anticancer effects in glioblastoma cells.

ABSTRACT

Glioblastomas (GBs) are highly aggressive and malignant brain tumors, which are highly resistant to conventional multimodal treatments, leading to their abysmal prognosis. Herein, we designed two organometallic half-sandwich Ru(ii)-η6-p-cymene complexes containing Schiff bases derived from 3-aminoquinoline and 2-hydroxy-benzaldehyde (L1) and 2-hydroxy-naphthaldehyde (L2), namely [Ru(η6-p-cymene)(L1)Cl] (1) and [Ru(η6-p-cymene)(L2)Cl] (2), respectively, and studied their activity on GB cells. Both complexes were structurally characterized using single-crystal X-ray diffraction, which exhibited their half-sandwich three-legged piano-stool geometry. Furthermore, we studied their physicochemical behavior, solution speciation, aquation kinetics, and photo-substitution reactions using various spectroscopic methods. The complexes exhibited a moderate binding affinity with calf-thymus (CT)-DNA (Kb ∼ 105 M-1). The complexes effectively interacted with human serum albumin (HSA) (K ∼ 105 M-1) with preferential tryptophan binding, as determined via synchronous fluorescence studies. The in vitro studies showed their significant antiproliferative activity against an aggressive human GB cell line, LN-229 (IC50 = 22.8 µM), with moderate selectivity relative to normal mouse fibroblast L929 cells. Notably, [Ru(η6-p-cymene)(L1)Cl] (1) exhibited a higher selectivity index (S.I.) than [Ru(η6-p-cymene)(L2)Cl] (2) and cisplatin. We evaluated the clonogenic potential of the GB cells using a colony formation assay in the presence of complex 1. Excitingly, it showed ∼75% inhibition of the clonogenic potential of GB cells at the IC50 concentration. Complex 1 also effectively lowered the migratory potential of the GB cells, as assessed by the wound healing assay. The studied compound led to the apoptosis of GB cells, as evidenced by nuclear condensation, blebbing, and enhanced caspase 3/7 activity, and thus has anticipated utility in the treatment of GBs using photochemotherapy.