Synthesis And Activity Of Half-sandwich Iridium(?) Nitrogen Heterocyclic Carbene Anti-tumor Complexes

The incidence and mortality of cancer are increasing year by year,which greatly threatens human health.Therefore,the research progress of antitumor drugs has been a hot spot of concern.Among them,metal-centered platinum antitumor drugs have been widely used clinically,but with a series of serious side effects such as poor selectivity,strong drug resistance and nephrotoxicity.Even so,the successful clinical use of platinum has accelerated the search for alternatives to drugs with better targeting capabilities and new mechanisms of action.Among them,iridium^? complexes show great potential in antitumor drugs because of their good stability and wide range of biological properties.Herein,we synthesized and characterized a series of imidazole and benzimidazole half-sandwich Ir^? N-heterocyclic carbene?NHC?antitumor complexes,the general formula of which can be expressed as[??⁵-Cp*?Ir?C^C?Cl]and[??⁵-Cp^x?Ir?C^N?Cl]Cl(Cp^x:pentamethylcyclopentadienyl?Cp*?or biphenyl derivative(Cp^xbiph);C^C:four NHC chelating ligands containing phenyl rings at different positions;C^N:seven different imidazole and benzimidazole NHC chelating ligands),respectively.The structures of chelating ligands and complexes were characterized by nuclear magnetic resonance spectroscopy?¹H NMR?,electrospray ionization mass spectrometry?ESI-MS?and elemental analysis,etc.The cytotoxicity of the half-sandwich complex on A549 cells was detected by MTT assay.The hydrolysis and catalytic activity of half-sandwich Ir^? complexes were studied by UV-Vis and ¹H NMR,and the interaction of Ir^? complexes with bovine serum albumin?BSA?was investigated by fluorescence and UV-Vis spectrometry.In addition,the effects of half-sandwich Ir^?II complexes on cell cycle,apoptosis,reactive oxygen species?ROS?level and mitochondrial membrane potential?MMP?in A549 cells were determined by flow cytometry.Due to its inherent luminescence,laser confocal focus can show the dependent mechanism and effective targets of the complexes entering the cells.After all half-sandwich Ir^? NHC antitumor complexes were treated with A549 cells for 24 h,complexes?except 1A-3A and 1B?showed antitumor activity superior to cis-platin.The complex has good stability in aqueous solutions and interacts with BSA by static quenching.Among them,complexes 2,3,4B and 7B catalyzes the conversion of NADH to NAD⁺,and the maximum turnover number values?TONs?is 15.2,which can induce the increase of intracellular ROS level.Ir^? complexes arrests A549 cells in sub-G₁ and S phase,decrease mitochondrial membrane potential significantly and further induce apoptosis.The complexes?3,4B and 7B?were observed by confocal microscopy,mainly targeting intracellular lysosomes,which the Pearson co-localization coefficients shown after the test were 0.82,0.72 and 0.71,respectively.Studies on the mechanism of action indicate that the complexes enter the cells through energy-dependent cellular uptake mechanism.