In vitro investigation of ruthenium(II) metallodrugs for the treatment of cancer

Abstract

Synthesis of metallodrugs is one of the various approaches that have been generated to fight cancer, overcome platinum resistance, and reduce drug toxicity to improve patient outcomes. Exploring new metal-based compounds, including those of iridium (Ir), osmium (Os), ruthenium (Ru), and rhodium (Rh), have heightened due to their promising activity in many types of cancer cells. Piano stool complexes are examples of ruthenium(II) that have been extensively studied due to their unique mechanisms of action, influence on mitochondrial function and increased reactive oxygen species level (ROS). However, the biological activities of many piano stool complexes remain unexplored. This study explores the potency of the ruthenium piano stool complex [RuCl(p-cymene)(R,R-TsDPEN)]and its fluorinated analogue [RuCl(p-cymene)(R,R-FsDPEN)] alongside precursor reagents (TsDPEN ligand and Ru pcymene dimer compound [Ru(p-cymene)Cl2]2) towards a series of ovarian cancer cell lines. Complex 1 and fluorinated Ru complex 2 displayed moderate antiproliferative activities in ovarian cell lines with an IC50 range of 10.2 ± 0.5 - 66 ± 0.1 µM and can overcome the cisplatin resistance in A2780cis (cisplatin-resistant cancer cells). Moreover, Ru complexes exhibited moderate potencies in p53-mutant and p53 wild-type cell lines, suggesting that the mechanism(s) of action is unlikely to involve p53, an essential factor in the mechanism of action of cisplatin. This study showed that the presence of fluorine atoms in Ru complex 2 significantly increased the accumulation of Ru in A2780 cells, imparting improved anticancer activity (IC50 =16 ± 0.1 µM) and greater selectivity for cancer cells over non-cancerous cells. In addition, increased ruthenium accumulation in A2780 cells significantly increased the intracellular zinc concentration. The findings of this study provide promising anticancer properties for fluorinated Ru complex 2, which should be considered for further biological evaluation by using different cancer cell lines in different experiments.