Shumiao Zhang

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.

Functionalized Ultrasmall Fluorinated Graphene with High NIR Absorbance for Controlled Delivery of Mixed Anticancer Drugs

Fluorinated graphene (FG) possess distinctively novel properties different from graphene and is suitable for many biomedical applications. However, the hydrophobic nature and inert properties of FG limit its further application as a biological material. Here we show the preparation of nano-sized FG (ca. 60u2005nm) that exhibits high NIR absorbance for photothermal therapy. In order to make it stable in physiological solutions, the FG is enriched with oxygen and followed by covalent binding with chitosan as a novel pH-responsive nanocarrier. Furthermore, controlled loading of two anticancer drugs, doxorubicin (DOX) and camptothecin (CPT) has been realized and the functionalized ultrasmall FG shows remarkably high cytotoxicity toward Hela cancer cells compared to that loaded with either CPT or DOX only. This work established nano-sized FG as a novel photothermal agent due to its small size and can be used a stimulus-responsive nanocarrier for mixed drug delivery and combined therapy.

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.

Novel iridium(III) iminopyridine complexes: synthetic, catalytic, and in vitro anticancer activity studies

Organometallic half-sandwich IrIII complexes of the type [(η5-Cpx)Ir(N^N)Cl]PF61–6, where Cpxu2009=u2009C5Me5 (Cp*), C5Me4C6H5 (Cpxph), C5Me4C6H4C6H5 (Cpxbiph), 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.

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.

Lysosome targeted drugs: rhodamine B modified N^N-chelating ligands for half-sandwich iridium(III) anticancer complexes

We designed and synthesized four rhodamine-modified half-sandwich iridium complexes ([(η5-Cpx)Ir(N^N)Cl]PF6). The fluorescence properties of the complexes were studied. Excitingly, the cytotoxicity of the complexes was superior to that of cisplatin for both A549 cells and HeLa cells. In particular, for A549 cells, the cytotoxicity of complexes 2 and 3 was 5 or 6-fold higher than that of cisplatin. Interactions with ctDNA and BSA have been investigated. The results show that the interaction with DNA does not seem to be the main anticancer mechanism. A binding experiment between BSA and complexes was carried out using a UV spectrophotometer and a fluorescence spectrophotometer. The catalytic conversion of the coenzyme NADH to NAD+ has also been investigated for hydrogen transfer of the complexes. In addition, complex 3 was studied in cell experiments because of its good antiproliferative activity. In addition, the cell distribution and targeting mechanisms of these complexes were studied using confocal microscopy. Complex 3 can induce cell death by blocking the G0/G1 phase of the cell cycle, affecting the mitochondrial membrane potential, then entering the cells and specifically targeting lysosomes. These seem to contribute to the anticancer activity of the complexes.

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.

Lysosome-Targeted Chemotherapeutics: Half-Sandwich Ruthenium(II) Complexes That Are Selectively Toxic to Cancer Cells

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.

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.