Zhe Liu

Half-Sandwich Iridium(III) and Ruthenium(II) Complexes Containing P^P-Chelating Ligands: A New Class of Potent Anticancer Agents with Unusual Redox Features

A series of half-sandwich IrIII pentamethylcyclopentadienyl and RuII arene complexes containing P^P-chelating ligands of the type [(Cpx/arene)M(P^P)Cl]PF6, where M = Ir, Cpx is pentamethylcyclopentadienyl (Cp*), or 1-biphenyl-2,3,4,5-tetramethyl cyclopentadienyl (CpxbiPh); M = Ru, arene is 3-phenylpropan-1-ol (bz-PA), 4-phenylbutan-1-ol (bz-BA), or p-cymene (p-cym), and P^P is 2,20-bis(diphenylphosphino)-1,10-binaphthyl (BINAP), have been synthesized and fully characterized, three of them by X-ray crystallography, and their potential as anticancer agents explored. All five complexes showed potent anticancer activity toward HeLa and A549 cancer cells. The introduction of a biphenyl substituent on the Cp* ring for the iridium complexes has no effect on the antiproliferative potency. Ruthenium complex [(η6-p-cym)Ru(P^P)Cl]PF6 (5) displayed the highest potency, about 15 and 7.5 times more active than the clinically used cisplatin against A549 and HeLa cells, respectively. No binding to 9-MeA and 9-EtG nucleobases was observed. Although these types of complexes interact with ctDNA, DNA appears not to be the major target. Compared to iridium complex [(η5-Cp*)Ir(P^P)Cl]PF6 (1), ruthenium complex (5) showed stronger ability to interfere with coenzyme NAD+/NADH couple through transfer hydrogenation reactions and to induce ROS in cells, which is consistent with their anticancer activities. The redox properties of the complexes 1, 5, and ligand BINAP were evaluated by cyclic voltammetry. Complexes 1 and 5 arrest cell cycles at the S phase, Sub-G1 phase and G1 phase, respectively, and cause cell apoptosis toward A549 cells.

Triphenylamine-Appended Half-Sandwich Iridium(III) Complexes and Their Biological Applications

Organometallic half-sandwich IrIII complexes of the type [(η5 -Cpx )Ir(N^N)Cl]PF6 (Cpx : Cp* or its phenyl Cpxph or biphenyl Cpxbiph derivatives; N^N: triphenylamine (TPA)-substituted bipyridyl ligand groups) were synthesized and characterized. The complexes showed excellent bovine serum albumin (BSA) and DNA binding properties and were able to oxidize NADH to NAD+ (NAD=nicotinamide adenine dinucleotide) efficiently. The complexes induced apoptosis effectively and led to the emergence of reactive oxygen species (ROS) in cells. All complexes showed potent cytotoxicity with IC50 values ranging from 1.5 to 7.1u2005μm toward A549 human lung cancer cells after 24u2005hours of drug exposure, which is up to 14u2005times more potent than cisplatin under the same conditions.

Imine-N-Heterocyclic Carbenes as Versatile Ligands in Ruthenium(II) p-Cymene Anticancer Complexes: A Structure-Activity Relationship Study

A family of novel imine-N-heterocyclic carbene ruthenium(II) complexes of the general formula [(η6 -p-cymene)Ru(C^N)Cl]PF6 - (where C^N is an imine-N-heterocyclic carbene chelating ligand with varying substituents) have been prepared and characterized. In this imine-N-heterocyclic carbene chelating ligand framework, there are three potential sites that can be modified, which distinguishes this class of ligand and provides a body of flexibilities and opportunities to tune the cytotoxicity of these ruthenium(II) complexes. The influence of substituent effects of three tunable domains on the anticancer activity and catalytic ability in converting coenzyme NADH to NAD+ is investigated. This family of complexes displays an exceedingly distinct anticancer activity against A549 cancer cells, despite their close structural similarity. Complexu20059 shows the highest anticancer activity in this series against A549 cancer cells (IC50 =14.36u2005μm), with an approximately 1.5-fold better activity than the clinical platinum drug cisplatin (IC50 =21.30u2005μm) in A549 cancer cells. Mechanistic studies reveal that complexu20059 mediates cell death mainly through cell stress, including cell cycle arrest, inducing apoptosis, increasing intracellular reactive oxygen species (ROS) levels, and depolarization of the mitochondrial membrane potential (MMP). Furthermore, lysosomal damage is also detected by confocal microscopy.

Nano-sized paramagnetic and fluorescent fluorinated carbon fiber with high NIR absorbance for cancer chemo-photothermal therapy

Nano-sized fluorinated carbon fiber possesses unique charge distribution and special chemical bonds and holds great promise in biomedicine. However, its synthesis remains a big challenge on account of the chemical inertness and strong hydrophobicity of C-F bonds. Herein, an up-bottom method to prepare nano-sized and water-soluble fluorinated carbon fiber oxide (FCO) with tunable lengths and adjustable fluorine levels was first developed. It was found that the effective control over structure and composition endowed the FCO with high photoluminescence (PL) and near-infrared (NIR) light absorbance, which was further employed to monitor the drug loading by turn-off PL and treat cancer by photothermal therapy (PTT). We also reported the first experimental example of paramagnetic FCO, whose novel paramagnetism was generated by point defects from fluorine invasion. Moreover, the FCO was noncovalently functionalized with polyvinylpyrrolidone, loaded with doxorubicin of high capacity (1.15 mg mg-1) and exhibited acid-triggered and photothermally enhanced drug release behavior. The application of FCO in cancer treatment achieved much better therapeutic effects than single chemotherapy or PTT. This work established FCO as a novel nano-carrier with high PL, NIR absorbance, paramagnetism, and drug loading capacity, and demonstrated its first application in cancer chemo-photothermal therapy.

Electronic effects on reactivity and anticancer activity by half-sandwich N,N-chelated iridium(III) complexes

The synthesis and characterization of a series of organometallic half-sandwich N,N-chelated iridium(III) complexes bearing a range of electron-donating and withdrawing substituents were described. The X-ray crystal structures of complexes 1, 3 and 5 have been determined. This work demonstrated how the aqueous chemistry, catalytic activity in converting coenzyme NADH to NAD+ and anticancer activity can be controlled and fine-tuned by the modification of the ligand electronic perturbations. In general, the introduction of an electron-withdrawing group (–Cl and –NO2) on the bipyridine ring resulted in increased anticancer activity, whereas an electron-donating group (–NH2, –OH and –OCH3) decreased the anticancer activity. Complex 6 bearing a strongly electron-withdrawing NO2 group displayed the highest anticancer activity (7.3 ± 1.2 μM), ca. three times as active as cisplatin in the A549 cell line. Notably, selective cytotoxicity for cancer cells over normal cells was observed for complexes 1 and 6. DNA binding does not seem to be the primary mechanism for cancer fighting. However, the aqueous chemistry, cell apoptosis and cell cycle, which show similar dependence on the ligand electronic perturbations as the anticancer activity, appear to together contribute to the anticancer potency of theses complexes. This work may provide an alternative strategy to enhance anticancer activity for these N,N-chelated organometallic half-sandwich iridium(III) complexes.

Half-sandwich IridiumIII N-heterocyclic carbene antitumor complexes and biological applications

Series of half-sandwich IrIIIN-heterocyclic carbene (NHC) antitumor complexes [(η5-Cp*)Ir(C^C)Cl] have been synthesized and characterized (Cp* is pentamethyl cyclopentadienyl, and C^C are four NHC chelating ligands containing phenyl rings at different positions). IrIII complexes showed potent antitumor activity with IC50 values ranged from 3.9 to 11.8u202fμM against A549 cells by the MTT assay. Complexes can catalyze the conversion of the coenzyme NADH to NAD+ and induce the production of reactive oxygen species (ROS), and bonding to BSA by static quenching mode. Complexes can arrest the cell cycle in G1 or S phase and reduce the mitochondrial membrane potential. Confocal microscopy test show complexes could target the lysosome and mitochondria in cells with the Pearsons colocalization coefficient of 0.82 and 0.21 after 12u202fh, respectively, and followed by an energy-dependent cellular uptake mechanism.

Novel and Versatile Imine-N-Heterocyclic Carbene Half-Sandwich Iridium(III) Complexes as Lysosome-Targeted Anticancer Agents

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 [(η5-Cpx)Ir(C^N)Cl]PF6- [Cpx = pentamethylcyclopentadienyl (Cp*) or tetramethyl(biphenyl)-cyclopentadienyl (Cpxbiph)] 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 IC50 (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 (IC50 = 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.

2,4-Bis[(2,6-diisopropylphenyl)imino]-3-methylpentan-3-ol

The compound 2,4-bis[(2,6-diisopropylphenyl)imino]-3-methylpentan-3-ol was synthesized with a yield of approximately 80% by the reaction of 2,4-bis(2,6-diisopropylphenylimino)pentan-3-one with trimethylaluminum, which was followed by hydrolysis with an aqueous NaOH solution. A chemoselective addition to the C=O bond occurred in this reaction. The structure was confirmed by X-ray crystallography. This new compound was also fully characterized by 1H, 13C-NMR spectroscopy and 1H-13C HSQC spectroscopy, mass spectrometry and elemental analysis.

[(η5-pentamethylcyclopentadienyl)(3-fluoro-N-methylbenzylamine-к1,N)dichlorido]iridium(III)

A half-sandwich iridium(III) complex containing 3-fluoro-N-methylbenzylamine ligands has been obtained by reaction of one equivalent of [(η5-Cp*)IrCl2]2 (Cp* = pentamethylcyclopentadienyl) with two equivalent of 3-fluoro-N-methylbenzylamine in very good yield. The structure of this complex was confirmed by X-ray crystallography, 1H-NMR, 13C-NMR spectroscopy, and elemental analysis.

Half-Sandwich Iridium and Ruthenium Complexes: Effective Tracking in Cells and Anticancer Studies

Half-sandwich metal-based anticancer complexes suffer from uncertain targets and mechanisms of action. Herein we report the observation of the images of half-sandwich iridium and ruthenium complexes in cells detected by confocal microscopy. The confocal microscopy images showed that the cyclopentadienyl iridium complex 1 mainly accumulated in nuclei in A549 lung cancer cells, whereas the arene ruthenium complex 3 is located in mitochondria and lysosomes, mostly in mitochondria, although both complexes entered A549 cells mainly through energy-dependent active transport. The nuclear morphological changes caused by Ir complex 1 were also detected by confocal microscopy. Ir complex 1 is more potent than cisplatin toward A549 and HeLa cells. DNA binding studies involved interaction with the nucleobases 9-ethylguanine, 9-methyladenine, ctDNA, and plasmid DNA. The determination of bovine serum albumin binding was also performed. Hydrolysis, stability, nucleobase binding, and catalytic NAD+/NADH hydride transfer tests for complexes 1 and 3 were also carried out. Both complexes activated depolarization of mitochondrial membrane potential and intracellular ROS overproduction and induced cell apoptosis. Complex 3 arrested the cell cycle at the G0/G1 phase by inactivation of CDK 4/cyclin D1. This work paves the way to track and monitor half-sandwich metal complexes in cells, shines a light on understanding their mechanism of action, and indicates their potential application as theranostic agents.