Design And Anticancer Application Of Ferrocene-modified Iridium (III)/ruthenium (II) Complexe

Malignant tumor is a worldwide public health problem,and its morbidity and mortality are increasing year by year.At present,the use of cisplatin as the representative metal-based drug in the chemotherapy of malignant tumors accounts for more than half of the total use,but with the widespread application,some of its drawbacks have gradually emerged,such as strong toxic side effects and drug resistance arising from long-term administration.Therefore,it is urgent to design and synthesize metallic anticancer drugs with different mechanisms of action from platinum-based drugs.Metal iridium(Ⅲ)and metal ruthenium(Ⅱ)complexes have shown promising applications in tumor therapy,and their targeting and anticancer activities can be effectively regulated by modulating their peripheral ligands.In view of this,in this paper,ferrocene units with good anticancer potential were introduced into the metal iridium(Ⅲ)class and metal ruthenium(Ⅱ)class complexes,and the cellular uptake mechanism,subcellular targeting and anticancer mechanism of the drugs were investigated by regulating the species of peripheral ligands of iridium(Ⅲ)and ruthenium(Ⅱ),which provided a structural basis for the further design and optimization of such anticancer complexes.Details are as follows:1.Four structurally modulated ferrocene-modified cyclometallic iridium(Ⅲ)bipyridine complexes were designed and prepared.Trans-configurational-based complexes showed the better anticancer potential than that of cis-based one.Compared with ferrocene-bipyridine ligands and cyclic iridium(Ⅲ)bipyridine complexes,the target complexes showed better activity against both A549 and Hela cancer cells,and the selectivity index indicated that the complex Ir2 had better selectivity than cisplatin,confirming the good synergistic effect of ferrocene and cyclic iridium(Ⅲ)complexes.Flow cytometric assays revealed that the target complexes induced apoptosis(both early and late apoptosis)in A549 cells,inhibited the cell growth cycle(G1 phase),catalyzed the oxidation of intracytoplasmic coenzymes(NADH),effectively decreased the mitochondrial membrane potential,led to a large accumulation of intracellular reactive oxygen species,and exhibited an anti-cancer mechanism of oxidation.Laser confocal assays confirmed that the complexes exhibited a non-energy-dependent cellular uptake mechanism and accumulated in lysosomes,inducing apoptosis in cancer cells.Protein blotting analysis further confirmed the existence of lysosomalmitochondrial as an anti-cancer channel.Nude mouse model experiments confirmed that the target complexes possess better in vivo anticancer activity and less toxicity than cisplatin,and have potential for further investigation as anticancer agents.2.Four ferrocene-modified half-sandwich structured metallic iridium(Ⅲ)acylhydrazone complexes and two ferrocene-modified half-sandwich structured metallic ruthenium(Ⅱ)acylhydrazone complexes were designed and prepared.Among them,the half-sandwich structured iridium(Ⅲ)complexes with acetyl ferrocene as the ligand showed better anti-value-added activity against A549 cancer cells and were less toxic to BEAS-2B cells than cisplatin,exhibiting superior selectivity over cisplatin.Flow cytometric assays confirmed that the target complexes could induce late apoptosis in A549 cancer cells,block the cell cycle in S phase,catalyze the induction of NADH oxidation,reduce the mitochondrial membrane potential,induce an increase in intracellular reactive oxygen species content,and exhibit an anti-cancer mechanism of oxidation.Laser confocal testing confirmed that the entry of the complexes into the cells was through a non-energy-dependent uptake mechanism,targeting the mitochondria and accumulating in the mitochondria,leading to apoptosis.In this project,we designed and synthesized a series of ferrocene-modified metallic iridium(Ⅲ)and ruthenium(Ⅱ)anticancer complexes,which were experimentally verified to have stronger antitumor activity than cisplatin and to specifically act on specific organelles to induce apoptosis in tumor cells,and their antitumor activity and toxic side effects were verified in in vivo experiments.