Stydy On Anticancer Activity And Mechanism Of Dawson Type Arsenic-molybdenum Polyoxometalates

Cancer is one of the most serious diseases that endanger human health.Traditional anticancer drugs are expensive and have serious side effects.Therefore,the preparation of high-efficiency and low-toxicity anticancer drugs has always been a research hotspot in the field of drug synthesis.Polymetallic oxides(POMs)are excellent molecular-based materials and inorganic anticancer drug candidates because of their nanometer size,rich chemical composition and fascinating topology,as well as their shearable properties,adjustable physicochemical properties and broad spectrum anticancer biological activity.On the other hand,trivalent arsenic compounds have good anticancer activity,and have a prominent role in inhibiting leukemia and digestive tract tumors,but the liver and kidney damage caused by their high toxicity limits the use of such drugs.In addition,V^V+can be introduced into the polyacid system in the form of a substituent to adjust the properties of the polyacid.In this paper,a series of arsenic cap-modified Dawson type polyacid derivatives were prepared by introducing different amounts of As^III/V^V into the polyacid backbone by solution method using Dawson type arsenomolybdate(H₆As₂Mo₁₈O₆₂)as the precursor,and the anticancer activities of polyacid compounds with different modification degrees and their mechanisms were investigated to reveal the relationship between composition,structure and anticancer activities.The main findings are as follows:1.Using H₆As₂Mo₁₈O₆₂ as the precursor,organic ligand as the inducer,and As^III/V^V+as the modification unit,five cases of functionally modified Dawson-type arsenomolybdates were prepared by adjusting the reaction conditions.The effects of solution p H,reaction temperature,reaction time and material ratio on the degree of polyacid modification of Dawson system were investigated.The results of crystal structure determination show that compounds 1,2,4,and 5 are arsenomolybdates modified with imidazole ligands,mono-arsenic caps,di-arsenic caps,and tri-arsenic caps,respectively;Compound 3 is a tri-vanadium substituted arsenomolybdate modified with a single arsenic cap.Characterization analysis proved that compounds 1-5 have accurate crystal structures,high chemical purity,and strong stability under physiological environment,which can be applied to the study of anticancer activity of polyacids.2.The anti-cancer activity and selectivity of compounds 1-5 against different cancer cells using the CCK-8 method for primary screening showed that they had better inhibitory activity(IC₅₀<10?M)against A549 and MCF7 cell lines,selectively killing cancer cells while being less toxic to normal cells.Flow cytometry assays of both cell lines with selected compounds at appropriate concentrations showed that the anticancer activity of compounds 1-5 was enhanced with the bonding of the modified units to the polyacid compounds,with the highest maximum apoptotic rates of 28.7%and 39.3%for the tri-vanadium substituted compound 3 against MCF7 and A549,respectively,and the highest maximum apoptotic rates of 30.0%and 42.9%for the tri-arsenic cap-modified compound 5,respectively.30.0%and 42.9%,respectively,but compound3 was much less toxic to normal cells.FITC/PI staining of compounds 1-5 on apoptotic cells of MCF7 cell line further confirmed that the arsenic cap modified compounds all exhibited higher activity than the unmodified precursors as well as lower cytotoxicity than Na As O₂,indicating that the implantation of As^III cap formed a good drug synergy with Dawson-type polyacids.Comparison of the properties of several compounds showed that the compounds exhibited different anticancer activity and toxicity depending on the amount of arsenic cap implantation,so the drug activity of Dawson derivatives could be regulated at the molecular level by changing the reaction conditions and controlling the amount of arsenic cap implantation.3.The results of western blot experiments showed that Dawson-type arsenic molybdenum polyphosphate induces apoptosis of A549 and MCF7 cells through two pathways:On the one hand,this arsenomolybdate induces the release of cytochrome c from the inner mitochondrial membrane by down-regulating the expression of the apoptosis suppressor gene Bcl-2,which is responsible for regulating the mitochondrial apoptotic mechanism,and up-regulating the expression of the pro-apoptotic gene Bax,both of which encode proteins that form heterodimers,thereby blocking the downstream transfer of electrons in the respiratory chain and thereby jeopardizing the function of the respiratory chain,while promoting the production of reactive oxygen species,as confirmed in subsequent assays of intracellular ATP and ROS have been confirmed.On the other hand,this class of compounds also showed activation of caspase-9 and caspase-3 kinases in the caspase family,and activated related apoptosis pathways in cancer cells.That is,the apoptosis initiator protein caspase-9,which is involved in the mitochondrial apoptosis pathway,heterologously activates the execution protein caspase-3,which amplifies the apoptotic signal and passes down to the nucleus,leading to the degradation of the nucleus and the breakage of DNA in the nucleus,and finally to the endogenous apoptosis of the cell.In addition,the results of cell scratch and Transwell experiments also indicated that Dawson-type arsenomolybdate has a good ability to resist cancer cell metastasis.