Study On The Synthesis And Mechanism Of Clonidamine-modified Half-sandwich Iridium Anticancer Complex

Cancer is one of the major diseases that endanger the safety of human life,There are many ways to treat cancer today,and chemical drug treatment?Chemotherapy?is one of the main ways to treat cancer.The use of metal complexes in cancer chemotherapy drugs for cancer treatment has also gradually attracted people's attention due to the widespread clinical use of cisplatin.However,platinum drugs have shortcomings such as drug resistance and cytotoxicity.Designing and synthesizing a metal complex with a broad anticancer spectrum and small toxic side effects has gradually become the common desire of metal anticancer researchers.Metal iridium complexes have gradually gained people's attention because of their broad anti-cancer spectrum and some of the complexes'toxic and side effects.As a clinical antitumor drug,lonidamine and its derivatives have become the first choice for drug research and development because of its low toxicity to normal cells and specific targeting.In view of this,this article designed and synthesized a semi-sandwich structure metal iridium anti-cancer complex modified by lonidamine,and studied its anti-tumor mechanism,as follows:In this study,we designed and synthesized 5 kinds of ligands of lonidamine derivatives with lonidamine as the precursor,and combined with dimers of half-sandwich transition metal iridium to obtain 10 kinds of amine derivatives The modified half-sandwich metal iridium complex was characterized by nuclear magnetic resonance spectroscopy,mass spectrometry and elemental analysis.The antitumor activity of 10target complexes,2 half-sandwich transition metal iridium dimers,and 2 lonidamine precursor ligands were evaluated by MTT method.The results showed that at the same concentration,the IC₅₀ value of the two lonidamine precursor ligands was greater than100 and the IC₅₀ value of the two iridium dimers was greater than 50.The IC₅₀ value of the complex on the A549 cells after the precursor ligand of clonidine and the metal iridium dimer was between 7.9-30.1,indicating that the chelation of the two enhanced the antitumor activity of the complex.Serum protein binding experiments confirmed that the target complex can be transmitted through serum proteins in a static binding mode.Stability experiments in solution confirmed that the iridium-chlorine bond is the active center of such complexes.In addition,through the evaluation of apoptosis,mitochondrial membrane potential,cell cycle,catalytic coenzyme oxidation and other experiments have confirmed the anti-tumor mechanism of target complex oxidation,and ultimately lead to tumor cell apoptosis.The laser confocal test shows that the complex enters the cell by endocytosis,effectively accumulates in the lysosome,and causes damage to the lysosome,leading to tumor cell death.In conclusion,the semi-sandwich metal iridium complex modified with lonidamine derivatives is expected to serve as a diagnostic and therapeutic platform for novel lysosomal targeted antitumor drugs.