化学
谷胱甘肽
体内
体外
细胞凋亡
细胞内
生物化学
脂质过氧化
氧化应激
分子生物学
立体化学
酶
生物
生物技术
作者
Yuchao Yuan,Chuanlin Shi,Xiaoyun Wu,Wenlong Li,Chunxia Huang,Lijun Liang,Jing Chen,Yi Wang,Yun-Jun Liu
标识
DOI:10.1016/j.jinorgbio.2022.111820
摘要
Combining the ligand NPIP (2-(2-nitrophenyl)-1H-imidazo[4,5-f][1,10]phenanthroline) with piq (1-phenylisoquinoline) and bzq (benzo[h]quinolone) gave [Ir(piq)2(NPIP)](PF6) (Ir1), and [Ir(bzq)2(NPIP)](PF6) (Ir2). The newly synthesized complexes were characterized by high-resolution mass spectrometry (HRMS), 1H NMR and 13C NMR. The complexes showed high antiproliferative activity against B16 cells. Three-dimensional (3D) cell model in vitro was used to evaluate the inhibitory effect of iridium (III) complex on B16 cells. The cellular uptake, mitochondrial localization, and intracellular distribution of the drugs confirmed that the iridium (III) complexes targeted the mitochondria, and the complexes can lead to the loss of mitochondrial membrane potential (MMP), increases the intracellular ROS content, further induces apoptosis. We also found that Ir1 and Ir2 can trigger the release of damage-associated molecular patterns (DAMPs) (cell surface calreticulin (CRT), heat-shock protein 70 (HSP70) and high mobility group box 1 (HMGB1)). In addition, Ir1 and Ir2 inhibited glutathione (GSH) synthesis and thus induced oxidative stress, Ir1 and Ir2 promoted malondialdehyde (MDA) production which is the stable metabolite of lipid peroxidation products. Finally, mice xenograft assay was performed to demonstrate that the complex shows higher antitumor activity in vivo than cisplatin. The inhibitory rates for cisplatin and Ir1 are 38.95% and 69.67%, respectively.
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