Monofunctional dimetallic Ru(η6-arene) complexes inhibit NOTCH1 signaling pathway and synergistically enhance anticancer effect in combination with cisplatin or vitamin C

ONS donor ligands L1-L4 were utilized in the preparation of monofunctional dimetallic Ru(eta 6-arene) complexes (C1-C4). These ONS donor ligand based novel tricoordinated Ru(II) complexes bearing eta 6-arene co-ligand were prepared for the first time. The current methodology resulted in excellent isolated yields and these complexes were characterized in detail by different spectroscopic and spectrometric techniques. The structures of C1-C2 and C4 were characterized in solid state by single crystal X-ray analysis. The in vitro anticancer analyses showed these novel complexes suppressed the growth of breast (MCF-7), liver (HepG2) and lung (A549) cancer cells. C2 suppressed the growth of these cells in dose-dependent manner revealed form the MTT and crystal violet cell viability assays. Moreover, C2 was observed the most potent complex that was used further in detailed mechanistic analyses in cancer cells. C2 showed good cytotoxic activity at 10 mu M dose level as compared to cisplatin or oxaliplatin in these cancer cells. We observed morphological changes in cancer cells upon treatment with C2. Moreover, C2 suppressed the invasion and migration ability of cancer cells. C2 induced cellular senescence to retard cell growth and suppressed the formation of cancer stem cells. Importantly, C2 showed synergistic anticancer effect in combination with cisplatin and Vitamin C to further inhibit cell growth which suggested the potential role of C2 in cancer therapy. Mechanistically, C2 inhibited NOTCH1 dependent signaling pathway to suppress cancer cell invasion, migration and cancer stem cells formation. Thus, these data suggested potential role of C2 in cancer therapy by targeting NOTCH1-dependent signaling to suppress tumorigenesis. The results obtained in this study for these novel monofunctional dimetallic Ru(eta 6-arene) complexes showed their high anticancer potency and this study will pave to further cytotoxicity exploration on this class of complexes.

Automated summary

ONS donor ligands L1-L4 were used to prepare mono-functional dimetallic Ru(η6-arene) complexes (C1-C4). These complexes, which contain novel tridentate Ru(II) complexes with η6-arene co-ligand, were synthesized with high yields and characterized by various spectroscopic techniques. In vitro anticancer assays demonstrated that C2, the most potent complex, exhibited dose-dependent growth inhibition against breast, liver, and lung cancer cells. Furthermore, C2 showed cytotoxic activity comparable to cisplatin and oxaliplatin, induced morphological changes, and suppressed invasion, migration, cell senescence, and cancer stem cell formation. Combination treatment of C2 with cisplatin and Vitamin C demonstrated synergistic anticancer effects, suggesting its potential application in cancer therapy. Mechanistically, C2 inhibited NOTCH1-dependent signaling pathway, thereby suppressing tumorigenesis. These findings highlight the high anticancer potency of these novel Ru(η6-arene) complexes and provide a basis for further exploration of their cytotoxicity.