期刊
ORGANOMETALLICS
卷 37, 期 17, 页码 2880-2889出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.organomet.8b00402
关键词
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资金
- Shandong Provincial Natural Science Foundation [ZR2018MB023]
- National Natural Science Foundation of China [21671118, 21706147]
- Taishan Scholars Program
- Key Laboratory of Polymeric Composite AMP
- Functional Materials of the Ministry of Education [PCFM-2017-01]
- excellent experiment project of Qufu Normal University [jp201705]
We herein report the synthesis, characterization, and anticancer activity of a series of iridium(III) and ruthenium(II) half-sandwich complexes of the type 6 [(Cp-x/arene)M((PO)-O-boolean AND)Cl]PF6 (M = Ir, Cp-x = pentamethylcyclopentadienyl (Cp*) or its phenyl (Cp-xPh = C5Me4C6H5) or biphenyl (Cp-xbiPh = C5Me4C6H4C6H5) derivatives; M = Ru, arene = p-cymene (p-cym); (PO)-O-boolean AND = phosphine phosphonic amide ligand (PPOA)). The X-ray crystal structures of all complexes, in which the ligand can form six-membered rings with the metal center, have been determined. All of the complexes show remarkable anticancer activities toward HeLa and A549 cancer cells, activities which are higher than that of the clinical anticancer drug cisplatin. The incorporation of phenyl substituents on the Cp* ring for iridium(III) complexes results in little variation in their anticancer activities. These results can be attributed to the combinatorial action of the metal and PPOA ligand. Hydrolysis and DNA cleavage are not the major mechanisms of action. These complexes show potent catalytic activity in the transfer hydrogenation of NADH to NAD(+). Additionally, complexes [(eta(5)-C5Me5)Ir((PO)-O-boolean AND)Cl]PF6 (1) and [(eta(6)-p-cym)Ru((PO)-O-boolean AND)Cl]PF6 (4) arrest cell cycles at S and G(2)/M phase and S phase, respectively. Complexes 1 and 4 both can induce apoptosis of HeLa cancer cells. Reactive oxygen species (ROS) and mitochondrial membrane potential tests were also performed to explore the mechanism of action. When the concentration of the complexes is increased, the amount of reactive oxygen species (ROS) increases dramatically and the mitochondrial membrane potential decreases significantly in HeLa cancer cells. Overall, cell stress including cell cycle perturbation, apoptosis induction, increase in ROS level, and loss of mitochondrial membrane potential contributes to the anticancer potency of these complexes. Interestingly, the use of confocal microscopy provides insights into the microscopic mechanism in which the typical and most active complex 1 can damage lysosomes. This type of complex represents a potent platform for development of metal anticancer drugs.
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