Membrane Localized Iridium(III) Complex Induces Endoplasmic Reticulum Stress and Mitochondria-Mediated Apoptosis in Human Cancer Cells
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- 作者：Rui Cao ; Junli Jia ; Xiaochuan Ma ; Ming Zhou ; Hao Fei
- 刊名：Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：May 9, 2013
- 年：2013
- 卷：56
- 期：9
- 页码：3636-3644
- 全文大小：439K
- 年卷期：v.56,no.9(May 9, 2013)
- ISSN：1520-4804
文摘
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 NN ligand based on a structure [Ir(ppy)2(NN)]+ (ppy = 1-phenyl-pyridine; NN = 2,2鈥?bipyridine (bpy, 1) or phenanthroline (phen, 2) or 4,7-diphenyl-1,10- phenanthroline (DIP, 3)). As the size of coordinated NN 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 IC50s 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鈥揳ctivity optimization on these novel Ir(III) complexes as emerging cancer therapeutics.