Synthesis Of Clickable Iridium Hydrogen Complexes And Their Antitumor Activity Research

Recently,anticancer metallodrugs are receiving increasing attention for their high cytotoxicity and targeting activities.Iridium compounds are one of the most important metal classes.In this paper,three new types of iridium hydride complexes with clickable ligands were designed and synthesized.The anticancer activity and anticancer mechanisms were investigated.Cellular imaging and localization by using their clickable groups were also explored.First,we synthesized three kinds of new iridium hydride complexes 1-a,1-b and1-AMP with PBN derivative ligand.The anticancer test showed that complex 1-AMP with azide group exihibited the best anticancer activity to human ovarian cancer A2780cells(IC₅₀:0.89?M).Subsequent studies on anticancer mechanism revealed that 1-AMP induced production of reactive oxygen species,catalyzed redox process of NAD⁺/NADH processing and destroyed cellular DNA structure in nuclear.Finally,the clickable azide unit in 1-AMP were used to conduct copper-catalyzed cycloaddition reactions of azide and alkynyl groups and strain-promoted cycloaddition of azide and cycloalkyne reaction in cells.The results of two imaging methods both revealed that 1-AMP was mainly located in the mitochondria.Second,we synthesized three novel iridium hydride complexes 2a,2b and 3b with free nitrone unites via C-H activation.The anti-tumor cell proliferation assay showed that compound 2a exihibited the best antitumor activity to human ovarian cancer cell A2780 cells(IC₅₀:0.69?M).Mechanistic studies showed that complex 2a induced about 29.7 times of reactive oxygen species(ROS)production.Then we performed a strain-promoted alkynyl-nitrone cycloadditionreaction of complexes 2a and 2b by using nitrone units,and the fluorescence intensities after reaction were about 2 times higher than background probes.Location studies of complex 2a and 2b indicated that SPANC reaction products were located in the mitochondria.Besides,shrunking mitochondria in 2a-treated cells was observed by transmission electron microscopy.Finally,proteomics analysis revealed that the synthetases and dehydrogenases in the mitochondria of A2780 cells may be the key targets of 2a towards A2780 cells.Besides,bioinformatics analysis indicated that 2a might induce ferroptotic cell death in cancer cells.Finally,we synthesized a novel biofunctional iridium-hydrogen complex 2-N3with both azide and nitrone ligands.The IC₅₀ value of A2780 against human ovarian cancer cell A2780 was 0.98?M,17.42 times higher than cisplatin.The cell distribution displayed a 18.5%distribution of compound 2-N3 in the nucleus,indicating an enhanced ability to penetrate the nuclear membrane when compared with complexes 1-AMP and 2a.The preliminary study of anticancer mechanism revealed that 2-N3induced production of reactive oxygen species in A2780 cells,and changed the morphology of mitochondria and further induced apoptosis.The results of the copper-catalyzed cycloaddition reaction using azide groups in compound 2-N3 showed that 2-N3 was obviously located in the nucleus and nucleolus.Besides,the apototic cell morphology and morphological damage to various organelles induced by 2-N3 were also observed via transmission electron microscopy.Finally,proteomics analysis revealed that 2-N3 affected key enzymes involved in the transcription and transcription of DNA.Bioinformatics analysis also indicated that 2-N3 activated ECM-receptor interaction pathway.Therefore,in this study,we developed clicakable iridium complexes by introducing the coordination of clickable groups to iridium catalysts and conducted chemical click reaction in cells to reveal the location of complexes.This strategy provided a new approach for designing multifunctional metallodrugs.Proteomics study of metal drugs in cancer cells provided new research methods for discovering and exploring new mechanisms of metal drugs.