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, Department of Chemistry and Chemical Engineering, Qufu Normal University, Qufu 273165, China.
Dalton Trans. 2018 Nov 13;47(44):15772-15782. doi: 10.1039/c8dt02963f.
In this study, six half-sandwich luminescent iridium (Ir) and ruthenium (Ru) anticancer complexes bearing P^P-chelating ligands 1,2-bis(diphenylphosphino)benzene (dppbz) and 1,8-bis(diphenylphosphino)naphthalene (dppn) were synthesized and characterized via1H-NMR spectroscopy, 31P-NMR spectroscopy, mass spectrometry, elemental analysis and X-ray crystallography. All the complexes displayed more potent anticancer activity than cisplatin towards A549 lung cancer cells and HeLa cervical cancer cells, especially the most potent iridium complex Ir3, which was 73 times more potent than cisplatin against A549 cells. Different from cisplatin, no nucleobase adducts of Ir3 were detected. With the help of the self-luminescence of complex Ir3 and confocal microscopy, it was observed that Ir3 efficiently penetrated into the A549 cells via energy-dependent active transport, and specifically accumulated in lysosomes, affected the permeabilization of the lysosomal membranes and induced caspase-dependent cell death through lysosomal damage. Both apoptosis and autophagy of the A549 cells were observed. The reactive oxygen species (ROS) elevation, reduction of the mitochondrial membrane potential and cell cycle arrest at the G0/G1 phase also contributed to the observed cytotoxicity of Ir3. We demonstrate that these half-sandwich Ir and Ru anticancer complexes have different anticancer mechanism of action from that of cisplatin, which can be developed as potential multifunctional theranostic platforms that combine bioimaging and anticancer capabilities.
在这项研究中，合成并通过 1H-NMR 光谱、31P-NMR 光谱、质谱、元素分析和 X 射线晶体学对六种具有 P^P-螯合配体 1,2-双(二苯基膦基)苯（dppbz）和 1,8-双(二苯基膦基)萘（dppn）的半三明治发光铱（Ir）和钌（Ru）抗癌配合物进行了表征。所有配合物对 A549 肺癌细胞和 HeLa 宫颈癌细胞的抗癌活性均强于顺铂，尤其是最有效的 Ir 配合物 Ir3，对 A549 细胞的活性比顺铂高 73 倍。与顺铂不同，未检测到 Ir3 的核苷碱基加合物。借助配合物 Ir3 的自发光和共聚焦显微镜，观察到 Ir3 通过能量依赖性主动转运有效地穿透 A549 细胞，并特异性地积累在溶酶体中，通过溶酶体损伤影响溶酶体膜的通透性并诱导 caspase 依赖性细胞死亡。观察到 A549 细胞的凋亡和自噬。活性氧（ROS）的升高、线粒体膜电位的降低以及细胞周期停滞在 G0/G1 期也导致了 Ir3 的观察到的细胞毒性。我们证明，这些半三明治 Ir 和 Ru 抗癌配合物与顺铂的抗癌作用机制不同，可开发为具有生物成像和抗癌功能的多功能治疗平台。
