Synthesis Of Hepatocyte Targeting Chelating Agent And The Study Of Biological Activities

Copper is an important element necessary for life activities,and the liver is the main organ for copper storage and metabolism in the body.Copper overload is an important risk factor leading to the occurrence and development of liver cancer.It will cause a series of serious consequences:the copper deposited in the liver not only directly causes cytotoxicity,but also causes the intracellular H₂O₂ to produce a large number of hydroxyl free radicals through the Fenton reaction（·OH）,causing oxidative damage of cell membrane lipids and mitochondrial membrane lipids,causing abnormal cell proliferation,activating oncogenes,and ultimately inducing cancer;and cell oxidative damage further aggravates liver metabolic dysfunction,resulting in more copper deposition,leading to The vicious circle of copper metabolism disorders.Therefore,timely and effective removal of copper deposits in the liver is a necessary prerequisite for the restoration of copper metabolism,and it is also the final barrier to prevent normal liver cells from transforming into hepatocellular carcinoma and prevent the occurrence or spread of liver cancer.In this work,we covalently couple the synthetic thiosemicarbazone-like copper chelating agents with the hepatocyte targeting molecule lactobionic acid to design and synthesize a class of highly efficient Specific hepatocytes target copper chelator.The molecular structure was characterized by mass spectrometry（MS）,elemental analysis,carbon nuclear magnetic resonance spectrum(¹³C NMR),proton nuclear magnetic resonance spectrum（¹H NMR）,Fourier transform infrared spectroscopy（FT-IR）,etc.Then,the structure and properties of the chelating agent were studied by automatic potentiometric titration,ultraviolet spectroscopy（UV）and Fourier transform infrared spectroscopy（FT-IR）.Then we established a high-copper cell model by simulating the physiological environment of human liver cancer cells to study the cytotoxicity of chelating agents,the chelating performance of chelating agents on intracellular copper,the effect of chelating agents on intracellular copper enzyme activity,and chelating agents Effect on the apoptosis cycle of liver cancer cells.The research results show that:compared with other chelating agents,the copper chelating agent we designed and synthesized has a certain selectivity to copper ions,the copper coordination ability is moderate,and will not interfere with the normal function of copper enzymes such as SOD1;and the chelating agent has a positive effect on cells.It is less toxic,and can clear the deposited copper in the cells through chelation,and promote the apoptosis of HepG2 cells under the high copper model,and the grafting with lactic acid has the potential to achieve targeted drug delivery to the liver.Therefore,the chelating agent may be a potential targeted drug for alleviating or treating hepatocellular carcinogenesis due to copper deposition.