摘要
通过无机碘盐(MIn)与 cis-[Fe(CO)4I2]反应制备了 5个盐类化合物fac-M[Fe(CO)3I3]n(Mn+=Na+(1),K+(2),Mg2+(3),Ca2+(4),NH4+(5)),探讨了阳离子Mn+对fac-[Fe(CO)3I3]-阴离子的稳定性和细胞毒性的影响.通过傅里叶变换红外光谱(FTIR)监测,发现盐1～5在DMSO、D2O、生理盐水等介质中均能缓释CO,其释放动力学符合一级反应动力学模型;还发现溶液中碘离子的浓度和酸度对该阴离子的缓释CO性能也具有调节作用.通过噻唑蓝(MTT)实验评估了盐1～5对膀胱癌细胞的毒性,其24 h半抑制浓度(IC50)在25～43 μmol·L-1.与有机铵阳离子类的盐化合物相比,盐1～5在含水介质中的释放CO速率下降,毒性亦有下调.研究还发现这类fac-[Fe(CO)313]阴离子在缓释CO的同时释放碘自由基,并能导致线粒体活性氧(ROS)水平、Parkin蛋白表达均上调.铁死亡抑制剂(Ferrostatin-1和Liproxstatin-1)试验结果表明这类化合物可能引发铁死亡通路并促进肿瘤细胞死亡.
Abstract
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.
基金项目
国家自然科学基金(82104197)
浙江省自然科学基金(LY23B010002)
嘉兴市医学重点学科(2023-ZC-013)
嘉兴市泌尿系肿瘤精准诊治重点实验室(2020-mnzdsys)
嘉兴大学(CD70623036)
NETL
NSTL
万方数据