| 含C^N-螯合配体环戊二烯基铱抗癌配合物 |
| Potent cyclopentadienyl iridium anticancer complexes containing C^N-chelating ligands |
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| 摘要: 八个半三明治结构环戊二烯基金属铱配合物[(η5-Cpx)Ir(C^N)Cl]被合成、表征, 其中Cpx分别为四甲基环戊二烯基（C5Me4H），五甲基环戊二烯基（Cp*），四甲基（苯基）环戊二烯基（Cpxph），四甲基（联苯）环戊二烯基（Cpxbiph）, C^N为苯亚甲基甲胺（BIMA），N-(4-甲氧基苯亚甲基)苯胺（MBIA）。X-射线单晶衍射仪测出了三个配合物的单晶结构。所有配合物对Hela人宫颈癌细胞显示出很强的细胞毒性, IC50值为1.7到32.9 μmol/L。经检测Cpx铱配合物的抗癌活性顺序为Cpxbiph > Cpxph > C5Me4H > Cp*。配合物[(?5-Cpxbiph)Ir(BIMA)Cl]（A4）和 [(?5-Cpxbiph)Ir(MBIA)Cl]（B4）表现出了最高的抗癌活性，比临床铂类药物顺铂活性高4倍以上。经检测，铱配合物A1-B4 不与9-甲基腺嘌呤和9-乙基鸟嘌呤反应，与pBR322 DNA也没有作用，但这些配合物能够作为氢转移催化剂，将辅酶NADH转化为NAD 。机理研究表明1倍IC50浓度的配合物A4，B4处理Hela细胞时会引起明显的细胞凋亡和细胞周期的变化, 并大幅增加细胞内活性氧(ROS)的水平。 |
| 关键词: 半三明治配合物,环戊二烯基配体,铱,抗癌药物,ROS水平,细胞凋亡,细胞周期,还原态烟酰胺腺嘌呤二核苷酸 |
| 基金项目: 国家自然科学基金，泰山学者工程 |
| Abstract: Half-sandwich cyclopentadienyl IrIII complexes of the type [(η5-Cpx)Ir(C^N)Cl], {Cpx = C5Me4H, Cp*, tetramethyl(phenyl)cyclopentadienyl (Cpxph), tetramethyl(biphenyl)cyclopentadienyl (Cpxbiph), C^N = N-benzylidenemethylamine (BIMA), N-(4-methoxybenzylidene)aniline (MBIA)}, have been synthesized and characterized. Three X-ray crystal structures have been determined. All complexes showed potent cytotoxicity, with IC50 values ranging from 32.9 to 1.7 μmol/L toward Hela human cervical cancer cells. Their potency is in the trend: Cpxbiph > Cpxph > C5Me4H > Cp*. Complexes [(?5-Cpxbiph)Ir(BIMA)Cl] (A4) and [(?5-Cpxbiph)Ir(MBIA)Cl] (B4) displayed the highest potency, more than 4 times more active than the clinical platinum drug cisplatin. No binding to nucleobases 9-ethylguanine (9-EtG), 9-methyladenine (9-MeA) and pBR 322 DNA were detected. The ability of these iridium complexes to catalytic hydride transfer from the coenzyme NADH to NAD is studied. Complexes A4 and B4 cause cell apoptosis and arrest cell cycles at G1 phase when Hela cancer cells were treated with different IC50 concentrations of complexes, and increase the reactive oxygen species (ROS) dramatically, which appears to contribute to the anticancer activity. |
| Keywords: Half-sandwich complexes,cyclopentadienyl ligand,iridium, anticancer drug, ROS level, apoptosis, cell cycle arrest, NADH |
| 投稿时间：2017-04-29 修订日期：2017-05-19 |
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