Design And Biological Performance Characterization Of Metal Iridium Picolinic Acid/bipyridine Anti-tumor Drugs

Cancer has become the primary factor affecting human health,and the development of antitumor drugs is imminent.The clinical application of platinum drugs such as cisplatin,carboplatin and oxaliplatin has successfully stimulated the exploration of transition metal complexes with anticancer activity.The aim is to discover that it can broaden the scope of cancer treatment,reduce toxic and side effects,enhance selectivity,and New metal-based anticancer drugs that overcome platinum resistance.At present,the transition metal iridium has attracted wide attention of researchers due to its octahedral structure and low-spin d6 orbital.Here,we designed,synthesized,and tested theα-picolinic acid ligand-modified semi-sandwich iridium（Ⅲ）complexes[(η⁵-Cp^xbiph)Ir（O^N）Cl]and triphenylamine（TPA）-modified cyclometal iridium（Ⅲ）Complexes[Ir（ppy）2（N^N）]PF6.The structure and properties of the synthesized products were tested by nuclear magnetic resonance spectroscopy（H-spectrum,C-spectrum）,elemental analysis,mass spectrometry,ultraviolet spectroscopy,and fluorescence spectroscopy;the anticancer activity of the selected complexes was studied by MTT method,and the cells were analyzed in vitro.Tests（cell cycle,apoptosis,production of reactive oxygen species,and mitochondrial membrane potential）;the experiment also tracked the colocalization of the complexes in A549 cancer cells with the help of a laser confocal microscope.The details are as follows:Among them,theα-picolinic acid semi-sandwich iridium（Ⅲ）complex[(η⁵-Cp^xbiph)Ir（O^N）Cl]was designed and synthesized.Compared with cisplatin,which is widely used clinically,the antitumor activity ofα-picolinic acid semi-sandwich iridium（Ⅲ）complex(IC₅₀:4.41±0.43μM)on A549 lung cancer cells was shown to be up to five times higher by MTT assay.The semi-sandwich iridium（Ⅲ）complex can be transported by serum albumin,catalyzes the oxidation of nicotinamide-adenine dinucleotide（NADH）and induces the production of reactive oxygen species,which to some extent reveals the antitumor mechanism of complex oxidation.The semi-sandwich iridium（Ⅲ）complex can be transported through serum albumin and follows a dynamic quenching transport mechanism.The half-sandwich iridium（Ⅲ）complex enters A549 cells following an energy-dependent cellular uptake mechanism.The localization coefficients were 0.33 and 0.74,respectively,leading to lysosomal destruction and a decrease in mitochondrial membrane potential（ΔΨm）,and eventually induced tumor cell apoptosis.The introduction of TPA structural units can effectively regulate the lipid solubility（logP）of cyclometal iridium（Ⅲ）complexes,and confer potential biological activity,especially in the field of anticancer（the optimal value of IC50 is 4.34±0.01μM）.In addition,complex 4 shows certain selectivity for cancer cells and normal human cells.Cyclic metal iridium（Ⅲ）complexes can be transported through serum albumin and follow a static quenching transport mechanism(Kq:10¹33 M^-11 s^-1),which interferes with the cell cycle of G₀/G₁ phase and induces apoptosis.Good fluorescence characteristics effectively confirm that cyclometal iridium（Ⅲ）complexes follow a non-energy-dependent cellular uptake mechanism,accumulate in large amounts in lysosomes（colocalization coefficient>0.95）,and induce lysosomal damage,Eventually results in cell death.