Study On Anti-Melanoma Activity Of Iridium(?) Polypyridyl Complexes

At present,cancer is seriously threatening human health.Platinum-based metal anticancer drugs are widely used in the treatment of various cancers due to their high efficiency and broad spectrum of anti-cancer activity.The main mechanism of this type of drug is to inhibit DNA replication in cancer cells by binding to their DNA,thereby inducing apoptosis.The first approved platinum-based metal anticancer drug,cisplatin,is still the drug of choice for common cancers such as testicular cancer and ovarian cancer.However,cisplatin has a series of strong side effects that can cause great pain to patients receiving the relevant treatment.Not only that,long-term use of cisplatin can also cause cancer cells to develop resistance.This prompts people to start looking for safer and better-effect metal complex anticancer drugs.Researchers have proposed a variety of new strategies for the development of metal anticancer drugs.One of the main methods is to replace the core metal of complex.Iridium,a platinum-group transition metal,is a promising candidate.Iridium???has a high coordination number,which means that the ligand structure acceptable for its complex has a wide variety.At present,in the related studies of metal complexes,polypyridine ligands?bipyridyl,phenanthroline,etc.?have a very wide range of applications.Studies have shown that a variety of polypyridyl metal complexes have biological activities and their mechanisms of action are different.Based on previous work,our laboratory synthesized a series of Iridium???polypyridine complexes.In order to explore the anticancer activity and mechanism of action of this complex,we have studied its anti-melanoma activity.In this paper,we first characterized this series of complexes by UV absorption spectroscopy and fluorescence spectroscopy.Mouse melanoma cells?B16?were used to evaluate the anti-melanoma activity of each complex by the thiazolyl blue?MTT?method.The complex Ir-10,[Ir?2-Phenylquinoline?₂?1,10-Phenanthrolin-5-amine?]PF₆,having strong anti-melanoma activity and certain fluorescence intensity was screened out.Cell lines such as human hepatoma cells?HepG2?,mouse brain neuroma cells?Neuro-2a?,and human umbilical vein endothelial cells?HUVEC?were used to examine the cytotoxicity of Ir-10 against many different cell types.Flow cytometry and staining to observe the morphological changes of B16 cells were used to verify that Ir-10 can induce apoptosis.The distribution of Ir-10 in B16 cells was observed by fluorescence microscopy;the changes of reactive oxygen species?ROS?levels in cells under the influence of Ir-10 were determined;the binding ability of Ir-10 to DNA was considered using calf thymus DNA?ct-DNA?;the effect of Ir-10 on cell cycle was examined by flow cytometry.At last,a subcutaneous melanoma model in mice was established by subcutaneous injection of B16 cells into C57BL/6 mice.Through this model,the in vivo anticancer activity of Ir-10 was verified and examined whether it had toxic side effects on normal tissues.The results showed that Ir-10 with fluorescent properties not only have better anti-melanoma activity but also have a desirable inhibitory effect on cancer cells that were not sensitive to cisplatin.The mechanism of Ir-10 is different from that of cisplatin and other complexes,which may cause apoptosis in cells by stimulating the increase of ROS levels in the cells.Ir-10 can exert normal anticancer activity in tumor-bearing mice,but it also produces certain side effects.In summary,Ir-10 exhibits excellent anti-cancer activity in vitro and in vivo,which proves that the ruthenium???polypyridine complex is expected to become a new type of metal anticancer drug.The above results provide a reference for the related research of Iridium metal complexes,and also lay a foundation for further improvement of Iridium???polypyridyl complex structure.