Membrane Localized Iridium(III) Complex Induces Endoplasmic Reticulum Stress and Mitochondria-Mediated Apoptosis in Human Cancer Cells
Membrane Localized Iridium(III) Complex Induces Endoplasmic Reticulum Stress and Mitochondria-Mediated Apoptosis in Human Cancer Cells
复制标题
膜局部铱（III）复合物诱导人类癌细胞内质网应激和线粒体介导的细胞凋亡
DOI：
10.1021/jm4001665
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发表时间：
2013-05-09
影响因子：
7.3
通讯作者：
Fei, Hao
中科院分区：
文献类型：
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作者：
Cao, Rui;Jia, Junli;Fei, Hao
金属有机配合物的细胞行为和毒性效应在很大程度上取决于其外围配体。在本研究中，我们在[Ir（ppy）（2）（（NN）-N-boolean AND）]（+）结构的基础上，通过调节辅助N布尔AND N配体，合成了一系列新型的发光阳离子铱（III）配合物（ppy = 1-苯基-吡啶;（NN）-N-布尔AND = 2，2 '-联吡啶（bpy，1）或菲咯啉（phen，2）或4，7-二苯基-1，10-菲咯啉（DIP，3））。随着配位的（NN）-N-布尔AND配体的尺寸增加，络合物的吸光度/发射效率、量子产率、亲脂性和细胞摄取速率也增加，一般顺序为：3 > 2 > 1。所有三个配合物显示抗癌活性，与3表现出最高的细胞摄取效率和最大的细胞毒活性在几个癌细胞系的IC（50）低于顺铂。由于其强疏水性，死亡诱导物3被发现有利地积聚到内质网（ER）并引起细胞中的ER应激。应激内质网胞浆钙离子的快速释放扰乱了线粒体的形态和功能，启动了一条内在的凋亡途径。了解细胞死亡机制将有助于进一步优化这些新型Ir（III）配合物作为新兴癌症治疗剂的结构-活性。
The cellular behavior and toxicity effect of organometallic complexes depend largely on their peripheral ligands. In this study, we have synthesized a series of novel luminescent cationic iridium(III) complexes by tuning the ancillary N boolean AND N ligand based on a structure [Ir(ppy)(2)((NN)-N-boolean AND)](+) (ppy = 1-phenyl-pyridine; (NN)-N-boolean AND = 2,2'-bipyridine (bpy, 1) or phenanthroline (phen, 2) or 4,7-diphenyl-1,10- phenanthroline (DIP, 3)). As the size of coordinated (NN)-N-boolean AND ligand increases, absorbance/emission efficiency, quantum yields, lipophilicity, and cell uptake rates of the complexes also increase, in a general order: 3 > 2 > 1. All three complexes display anticancer activity, with 3 exhibiting the highest cellular uptake efficiency and the greatest cytotoxic activities in several cancer cell lines with IC(50)s lower than that of cisplatin. Because of its strong hydrophobic nature, the death inducer 3 was found to accumulate favorably to endoplasmic reticulum (ER) and to cause ER stress in cells. The fast cytosolic release of calcium from stressed ER disturbed the morphology and function of mitochondria, initiating an intrinsic apoptotic pathway. Understanding of the cell death mechanism would help further structure-activity optimization on these novel Ir(III) complexes as emerging cancer therapeutics.