Five inorganic monoiron(Ⅱ)carbonyl salts 1-5,fac-M[Fe(CO)3I3]n(Mn+=Na+(1),K+(2),Mg2+(3),Ca2+(4),NH4+(5))were prepared from the reactions of cis-[Fe(CO)4I2]precursor with the iodo salts(MIn),and developed as CO-releasing molecules(CORMs)for CO therapy of cancer.The decomposition of salts 1-5 with CO-release in DMSO,D2O,saline,and phosphonate buffer solution was investigated by the Fourier transform infrared(FTIR)spectroscopic monitoring.The corresponding kinetics for the decomposing of these salts were estimated by abiding by a first-order model.Cytotoxicity of the five salts was assessed on a bladder cancer cell line(RT112)by the methyl thiazolyl tetrazolium(MTT)assays for 24 h,with the half maximal inhibitory concentration(IC50)values of 25-43 µmol·L-1.Notably,varying a counter ion offac-[Fe(CO)3I3]-anion from an organic aminium to an inorganic cation unambiguously affects its stability and thus the cytotoxicity.Moreover,a mechanistic probing into the cytotoxicity of fac-[Fe(CO)3I3]-anion was paved.Interestingly,not only the produced iodine radicals but also the gaseous CO from the decomposition contributed to its cytotoxicity.Particularly,it was found that,with the treatment of the anion,the reactive oxygen species(ROS)level in the mitochondria significantly enhanced,and the mitochondria-related protein expression of Parkin was extremely upregulated.The ferroptosis inhibitor assays of Ferrostatin-1 and Liproxstatin-1 confirmed that these complexes evoked a ferroptosis-involved pathway to contribute to their cytotoxic-ity.Therefore,a mechanistic understanding of the cytotoxicity offac-[Fe(CO)3I3]-anion is proposed,which is stimu-lated by the decomposing of the anion,and thus manufactures the mitochondria-relevant activities such as fission,energy metabolism,and mitophagy,and evokes a pathway of ferroptosis,to lead severe cellular damage even death.
iron carbonyliodinecounter ion effectCO releasekineticscytotoxicityferroptosis
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