含C^N-螯合配体的环戊二烯基铱抗癌配合物(英文)

Potent Cyclopentadienyl Iridium Anticancer Complexes Containing C^N-chelating Ligands

合成、表征了8个半三明治结构环戊二烯基金属铱配合物[(η~5-Cpx)Ir(C^N)Cl],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)。测定了其中3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1.7~32.9μmol·L-1。经检测Cpx铱配合物的抗癌活性顺序为Cpxbiph>Cpxph>C5Me4H>Cp*。配合物[(η~5-Cpxbiph)Ir(BIMA)Cl](A4)和[(η~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p BR322 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。

Half-sandwich cyclopentadienyl Ir（lil） complexes of the type [（r/5-CpX）Ir（C^N）C1], （CpX=CsMe4H, Cp＊, tetramethyl（phenyl）cyclopentadienyl （CpXph）, tetramethyl （biphenyl）cyclopentadienyl （Cpxbiph）, C^N =N-benzylidene- methylamine （BIMA）, N-（4-methoxybenzylidene）aniline （MBIA））, have been synthesized and characterized. X-ray crystal structures of three complexes have been determined. All complexes showed potent cytotoxicity, with IC50 values ranging from 32.9 to 1.7 μmol· L-1 toward Hela human cervical cancer ceils. Their potency is in the trend： CpXbiph〉Cpxph〉C5ne4H〉Cp＊. Complexes [（r/S-CpXhiph）Ir（BIMA）Cl] （A4） and [（η5-CpXbiph）Ir（nBIA）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 IC5o concentrations of complexes, and increase the reactive oxygen species （ROS） dramatically, which appears to contribute to the anticancer activity.