Two half-sandwich RuII diimine complexes combine features of bioimaging, anticancer and antimetastasis properties into one molecule. The complexes target mitochondria and damage mitochondrial integrity.
We, herein, report the synthesis, characterization, luminescence properties, anticancer, and antibacterial activities of a family of novel half-sandwich iridium(III) complexes of the general formula [(η-Cp)Ir(C^N)Cl]PF [Cp = pentamethylcyclopentadienyl (Cp*) or tetramethyl(biphenyl)-cyclopentadienyl (Cp)] bearing versatile imine-N-heterocyclic carbene ligands. In this complex framework, substituents on four positions could be modulated, which distinguishes this class of complex and provides a large amount of flexibility and opportunity to tune the cytotoxicity of complexes. The X-ray crystal structures of complexes 4 and 10 exhibit the expected "piano-stool" geometry. With the exception of 1, 2, and 11, each complex shows potent cytotoxicity, with IC (half-maximum inhibitory concentration) values ranging from 1.99 to 25.86 μM toward A549 human lung cancer cells. First, the effect of four positions bearing different substituents in the complex framework on the anticancer activity, that is, structure-activity relationship, was systematically studied. Complex 8 (IC = 1.99 μM) displays the highest anticancer activities, whose cytotoxicity is more than 10-fold higher than that of the clinical platinum drug cisplatin against A549 cancer cells. Second, their chemical reactivity including nucleobases binding, catalytic activity in converting coenzyme NADH to NAD, reaction with glutathione (GSH), and bovine serum albumin (BSA) binding is investigated. No reaction with nucleobase is observed. However, these iridium(III) complexes bind rapidly to GSH and can catalyze oxidation of NADH to NAD. In addition, they show moderate binding affinity to BSA and the fluorescence quenching of BSA by the iridium (III) complexes is due to the static quenching. Third, the mode of cell death was also explored through flow cytometry experiments, including cell cycle, apoptosis induction, reactive oxygen species (ROS) and mitochondrial membrane potential. It seems that cell cycle perturbation, apoptosis induction, increase of ROS level and loss of mitochondrial membrane potential together contribute to the anticancer potency of these complexes. Last, the use of confocal microscopy provides insights into the microscopic mechanism that the typical and most active complex 8 enters A549 lung cancer cells mainly through energy-dependent pathway and is located in lysosome. Furthermore, lysosome damage and nuclear morphology were detected by confocal microscopy. Nuclear condensation and apoptotic bodies may finally induce cells apoptosis. Interestingly, complex 8 also shows antibacterial activity against Gram-positive Staphylococcus aureus. This work may provide an alternative and effective strategy to smart design of potent organometallic half-sandwich iridium(III) anticancer drugs.
For the first time, a facile solvothermal method to synthesize COFs with a nanosized structure and bright fluorescence was reported to monitor drug loading with the naked eye and realize responsive release.
We herein report the synthesis, characterization, and anticancer activity of a series of iridium(III) and ruthenium(II) half-sandwich complexes of the type [(Cpx/arene)M(P^O)Cl]PF6 (M = Ir, Cpx = pentamethylcyclopentadienyl (Cp*) or its phenyl (Cpxph = C5Me4C6H5) or biphenyl (Cpxbiph = C5Me4C6H4C6H5) derivatives; M = Ru, arene = p-cymene (p-cym); P^O = 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 [(η5-C5Me5)Ir(P^O)Cl]PF6 (1) and [(η6-p-cym)Ru(P^O)Cl]PF6 (4) arrest cell cycles at S and G2/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.
Poor selectivity between cancer cells and normal cells is one of the major limitations of cancer chemotherapy. Lysosome-targeted ruthenium-based complexes target tumor cells selectively, only displaying rather weak cytotoxicity or inactivity toward normal cells. Confocal microscopy was employed for the first time to determine the cellular localization of the half-sandwich Ru complex.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.