Design And Anticancer Mechanism Of Coumarin-modified Metal Iridium Anticancer Compounds

Cancer is regarded as a special kind of"chronic disease".Only a handful of survivors have been cured after contracting cancer,causing people to"talk about cancer discoloration".The advent of platinum metal anticancer drugs in the field of anticancer and their results in clinical chemotherapy have prompted the development of metal anticancer drugs to attract more attention.However,the adverse reactions,drug resistance,low selectivity,and unclear mechanism of platinum drugs to the kidney limit their clinical application.Therefore,the development of new metal anti-cancer drugs with lower toxicity and more efficiency is imminent.Among them,the metal iridium(?)anti-cancer compounds has stable chemical properties,and has smaller side effects,wider anti-tumor spectrum and different anti-cancer mechanisms than platinum anti-cancer drugs.The study found that the flexible peripheral ligands of iridium(?)compounds have a great influence on their structure-activity relationship.In view of this,six"half-sandwich"metal iridium(?)compounds and six cyclometallic iridium(?)compounds were designed and synthesized using coumarin-salicylaldehyde Schiff base as the ligand in this paper.The composition and structure of the target compounds were characterized by nuclear magnetic resonance spectroscopy(¹H NMR,¹³C NMR,¹⁹F NMR),mass spectrometry and other modern physical methods.The stability,photophysical properties,biocatalytic properties and protein binding properties were tested by ultraviolet spectrophotometry and fluorescence spectrophotometry.The in vitro anti-tumor activity of these iridium(?)compounds on human lung cancer cells(A549),human cervical cancer cells(Hela)was measured by MTT method,and the antitumor mechanism and tissue targeting of the target compounds were studied by selecting the compound with better activity as follows:1.The"half-sandwich"metal iridium(III)compound has high anti-cancer activity,but its weaker fluorescence emission characteristics greatly limit the development of research.In view of this,this chapter designs,synthesizes and characterizes six fluorescent"half-sandwich"metal iridium(III)anticancer compounds([(?⁵-Cp*)Ir(O^N)Cl],Ir1-Ir6)containing coumarin-salicylic aldehyde Schiff base O^N chelating ligands.The introduction of coumarin units effectively increased the antitumor activity of these compounds(IC₅₀:9.9±0.1?M?40.7±12.9?M),among which the most active Ir2 was nearly twice that of clinical cisplatin.In addition,compounds containing methyl-substituted coumarin units(Ir1,Ir2,and Ir3)had better anti-tumor properties than their corresponding trifluoromethyl modified analogues(Ir4,Ir5,and Ir6),respectively.To understand these,the crystal structures of Ir1 and Ir4 were evaluated using quantum chemical calculations after considering them comprehensively.More interestingly,the introduction of coumarin units effectively improved the conjugation properties of O^N auxiliary ligands,resulting in the"half-sandwich"iridium(?)compounds exhibit rare green fluorescence.Based on the appropriate fluorescence properties,laser confocal irradiation revealed that the compound has an energy-dependent cellular uptake mechanism,accumulates in lysosomes(Pearson colocalization coefficient:?0.7),destroys the integrity of lysosomes,and induces apoptosis.Flow cytometry and UV-Vis spectroscopy confirmed that the compounds could reduce mitochondrial membrane potential,catalyze the oxidation of coenzymes(nicotinamide adenine dinucleotide),increase intracellular reactive oxygen species(ROS)levels,and exhibit the anti-tumor mechanism of oxidation.In addition,these compounds can block the metastasis of tumor cells.In a word,"half-sandwich"structure metal iridium(?)compounds is a kind of dual function(induction of apoptosis and cell migration resistance)of potential antitumor drugs.2.Cyclometallic iridium(?)compounds has good luminous performance,convenient in anti-cancer mechanism and cellular targeting the application of research,but their solubility is relatively small,active compared with"half-sandwich"iridium(?)compound is low.In this study,the coumarin-salicylaldehyde Schiff base was used as a chelating ligand to react with iridium(?)dimer to obtain the general structural formula([(ppy)₂Ir(O^N)],Ir7-Ir9)/([(ppy-CHO)₂Ir(O^N)],Ir10-Ir12)cyclometallic iridium(?)compounds,and its structure and composition were fully characterized.Thanks to the introduction of coumarin units,MTT assay showed certain anti-tumor activity against human lung cancer cells(A549),and some of the compounds were already superior to the commercial cisplatin.Using ultraviolet spectrum,fluorescence spectrum and flow cytometry proves that these compounds can effectively bind with BSA,destroy the cell cycle,resulting in a decline in mitochondrial membrane potential.At the same time,these complexes can catalyze the oxidation of NADH by REDOX and have good biocatalysis performance.In addition,thanks to its excellent fluorescence properties,cell imaging with laser confocal laser has confirmed that the complexes enter the cell in an energy-dependent manner and accumulates in lysosomes,causing lysosomal damage and ultimately causing cell apoptosis.