The Construction Of Fluorescent Metal Iridium Triphenylamine Anti-cancer System And The Study Of Its Anti-cancer Mechanism

Chemotherapy is the most commonly used treatment for cancer.At present,platinum drugs represented by cisplatin are the most widely used chemotherapeutic agents in clinic.However,while platinum drugs are widely used,many problems such as damage to normal cells and high drug resistance are becoming increasingly prominent.Iridium metal complexes have become potential substitutes for platinum drugs because of their high efficiency,high selectivity,clear targets and different mechanisms from platinum drugs.Therefore,we introduced the triphenylamine group with good fluorescence properties into the metal iridium complexes,constructed 15 half-sandwich metal iridium triphenylamine anticancer complexes,and studied their anticancer activity and mechanism.Firstly,six trans-double bonded half-sandwich iridium complexes were synthesized by introducing the triphenylamine.The introduction of triphenylamine can effectively improve the liposolubility of the complexes,and the anticancer activity of the complexes has been effectively improved.Compared with iridium metal complexes containing bipyridine,ethylenediamine and phenanthroline ligands,the IC₅₀ value of the complexes was effectively controlled at 1.5?7.1?M?cisplatin was 21.3?M under the same experimental conditions?.Complexes have catalytic activity for reducing coenzyme I?NADH?.The conversion of NADH into NAD⁺can produce reactive oxygen species?H₂O₂?to induce apoptosis.The binding constants of the compounds to BSA ranged from 2.33 to 22.56×10⁴ M^-1.In DNA replacement experiments,complexes also showed strong binding effect to DNA.In vitro cell experiments,complexes can induce early and late apoptosis of cells,and can effectively increase the level of reactive oxygen species?ROS?in cells which can lead to cell apoptosis and these confirm the mechanism of oxidation.Secondly,we discuss the effect of the introduction of triphenylamine into iridium metal complexes in a single bond mode by adjusting the number of introduced and the type of flexible chains at the end on their anticancer properties.By controlling the number of triphenylamine ligands and cyclopentadienyl substituents,the lipid solubility and anticancer activity of the complexes can be effectively regulated.The IC50 values of complexes 11-15 ranged from 1.2 to5.7?M.In vitro cell experiments,complexes can also effectively induce apoptosis,increase the level of reactive oxygen species and interfere with cell cycle.Because of the good targeting fluorescence of the complexes,we have studied the targeting and cell uptake mechanism of the complexes.The results showed that complexes 11 and 14 could effectively target lysosomes in cells.The localization coefficients of complexes 11 and 14 were 0.57 and 0.49,respectively.These indicated that the introduction of triphenylamine group which containing free electron and terminal methoxy group were facilitate the complex to target lysosomes.Drug uptake conforms to the energy mechanism,and low temperature can also inhibit cell absorption of complexes.It is confirmed that these complexes can cause lysosome damage by targeting lysosomes,and ultimately lead to apoptosis of cancer cells.In conclusion,the lipid solubility and anti-tumor activity of iridium complexes can be effectively regulated by reasonable regulation of the introduction mode and number of triphenylamine groups.In addition,introducing heteroatoms containing free electron pairs into the complexes can effectively improve the targeting of lysosomes,lead to lysosome damage,and then lead to cancer cell apoptosis.Therefore,iridium complexes containing triphenylamine group have good prospects in the field of metal anticancer.