Department of Chemistry and Chemical Engineering, Institute of Anticancer Agents Development and Theranostic Application, The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical Intermediates and Analysis of Natural Medicine, Qufu Normal University, Qufu, 273165, China.
J Biol Inorg Chem. 2018 Jul;23(5):819-832. doi: 10.1007/s00775-018-1578-0. Epub 2018 Jun 11.
Organometallic half-sandwich Ir complexes of the type [(η-Cp)Ir(N^N)Cl]PF 1-6, where Cp = CMe (Cp*), CMeCH (Cp), CMeCHCH (Cp), N^N is imionopyridine chelating ligand, were prepared and characterized. The X-ray crystal structure of complex 1 has been determined. Four compounds displayed higher anticancer potency than clinically used anticancer drug cisplatin against A549 cancer cells, especially complex 3 which is 8 times more active than cisplatin. No hydrolysis was observed by NMR and UV-Vis for complexes 3 and 6; however, these complexes show big differences in nucleobase binding, mainly decided by the imionopyridine chelating ligand. Complex 3 is stable in the presence of glutathione, but 6 reacted rapidly with glutathione. The octanol/water partition coefficients (log P) of 3 and 6 have been determined. In addition, these complexes display effective catalytic activity in converting coenzyme NADH to NAD by accepting hydride to form an Ir hydride adduct. The mechanism of actions of these complexes involves apoptosis induction, cell cycles arrest, and significant increase of reactive oxygen species levels in A549 cancer cells.
[(η-Cp)Ir(N^N)Cl]PF₆型有机金属半夹心 Ir 配合物，其中 Cp=CM e (Cp*)、CM e CH (Cp)、CM e CHCH (Cp)、N^N 是离子吡嗪螯合配体，已被制备和表征。配合物 1 的 X 射线晶体结构已被确定。四种化合物对 A549 癌细胞的抗癌活性均高于临床使用的抗癌药物顺铂，尤其是 3 号化合物，其活性是顺铂的 8 倍。NMR 和 UV-Vis 均未观察到配合物 3 和 6 的水解；然而，这些配合物在碱基结合方面表现出很大的差异，主要由离子吡嗪螯合配体决定。配合物 3 在谷胱甘肽存在下稳定，但 6 与谷胱甘肽反应迅速。3 和 6 的辛醇/水分配系数（log P）已经确定。此外，这些配合物在接受氢化物形成 Ir 氢化物加合物以将辅酶 NADH 有效转化为 NAD 方面表现出有效的催化活性。这些配合物的作用机制涉及凋亡诱导、细胞周期停滞以及 A549 癌细胞中活性氧水平的显著增加。
