The Experts below are selected from a list of 3039 Experts worldwide ranked by ideXlab platform
Zhe Liu - One of the best experts on this subject based on the ideXlab platform.
-
Lysosome-Targeted Phosphine-Imine Half-Sandwich Iridium(III) Anticancer Complexes: Synthesis, Characterization, and Biological Activity
2019Co-Authors: Yuliang Yang, Lihua Guo, Zhenzhen Tian, Yuteng Gong, Hongmei Zheng, Shaopeng Shi, Zhe LiuAbstract:The synthesis, characterization, and catalytic ability of converting Coenzyme NADH to NAD+ and the anticancer activity of half-sandwich iridium(III) complexes with general formula of [(η5-Cpx)Ir(P^N)Cl]PF6 (Cpx: Cp* or biphenyl Cpxbiph derivatives; P^N: various phosphine-imine ligands) were investigated. The crystal structure of the complex Ir4 showed a piano-stool geometry around the iridium(III) center. This type of iridium(III) complexes had sufficient stability in aqueous solution. Most of the complexes showed good anticancer activities toward A549 cancer cells, which were higher than the clinical drug cisplatin. In this series, complex Ir8 displayed the highest anticancer activity against A549 cells (IC50 = 4.7 μM), showing an approximately 4.5-fold more potent activity than cisplatin (IC50 = 21.30 μM). The structure–activity relationship study showed that the cytotoxicity of these complexes may be primarily attributed to the coordination between iridium(III) and the coordinating atoms, and the nature of the imine N-substituents may not be a major factor affecting cytotoxicity. Furthermore, this family of complexes causes cell death by cell stress, inducing apoptosis and necrosis, overproduction of reactive oxygen species, and disruption of the mitochondrial membrane potential. Most interestingly, the use of confocal microscopy provides insights into the microscopic mechanism that the typical complex Ir3 can penetrate into A549 cancer cells through a non-energy-dependent pathway and specifically distribute in lysosomes
-
Novel and Versatile Imine-N-Heterocyclic Carbene Half-Sandwich Iridium(III) Complexes as Lysosome-Targeted Anticancer Agents
2018Co-Authors: Yuliang Yang, Lihua Guo, Zhenzhen Tian, Yuteng Gong, Hongmei Zheng, Shumiao Zhang, Zhe LiuAbstract: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
-
formation of glutathione sulfenate and sulfinate complexes by an organoiridium iii anticancer complex
Inorganic chemistry frontiers, 2014Co-Authors: Zhe Liu, Peter J SadlerAbstract:The organoiridium(III) anticancer complex [(η5-Cpxbiph)Ir(phpy)py] (Cpxbiph = biphenyltetramethylcyclopentadienyl, phpy = phenylpyridine, py = pyridine) unexpectedly reacts with the tripeptide glutathione in the presence of Coenzyme NADH to give glutathione sulfenate (Ir–S(O)G) and sulfinate (Ir–S(O)2G) complexes. These new adducts may play a role in the anticancer activity of such organoiridium complexes.
-
the potent oxidant anticancer activity of organoiridium catalysts
Angewandte Chemie, 2014Co-Authors: Zhe Liu, Abraha Habtemariam, Ana M Pizarro, Bushra Qamar, Isolda Romerocanelon, Jessica M Hearn, Nicolas P E Barry, Guy J Clarkson, Peter J SadlerAbstract:Platinum complexes are the most widely used anticancer drugs; however, new generations of agents are needed. The organoiridium(III) complex [(η5-Cpxbiph)Ir(phpy)(Cl)] (1-Cl), which contains π-bonded biphenyltetramethylcyclopentadienyl (Cpxbiph) and C^N-chelated phenylpyridine (phpy) ligands, undergoes rapid hydrolysis of the chlorido ligand. In contrast, the pyridine complex [(η5-Cpxbiph)Ir(phpy)(py)]+ (1-py) aquates slowly, and is more potent (in nanomolar amounts) than both 1-Cl and cisplatin towards a wide range of cancer cells. The pyridine ligand protects 1-py from rapid reaction with intracellular glutathione. The high potency of 1-py correlates with its ability to increase substantially the level of reactive oxygen species (ROS) in cancer cells. The unprecedented ability of these iridium complexes to generate H2O2 by catalytic hydride transfer from the Coenzyme NADH to oxygen is demonstrated. Such organoiridium complexes are promising as a new generation of anticancer drugs for effective oxidant therapy.
-
reduction of quinones by NADH catalyzed by organoiridium complexes
Angewandte Chemie, 2013Co-Authors: Zhe Liu, Robert J Deeth, Jennifer S Butler, Abraha Habtemariam, Mark E Newton, Peter J SadlerAbstract:One electron at a time: Half-sandwich organometallic cyclopentadienyl–IrIII complexes containing N,N-chelated ligands can catalyze the reduction of quinones (Q), such as vitamin K3, to semiquinones (Q.ˉ) by Coenzyme NADH (see picture). DFT calculations suggest that the mechanism involves hydride transfer followed by two one-electron transfers and the unusual IrII oxidation state as a key transient intermediate.
Peter J Sadler - One of the best experts on this subject based on the ideXlab platform.
-
formation of glutathione sulfenate and sulfinate complexes by an organoiridium iii anticancer complex
Inorganic chemistry frontiers, 2014Co-Authors: Zhe Liu, Peter J SadlerAbstract:The organoiridium(III) anticancer complex [(η5-Cpxbiph)Ir(phpy)py] (Cpxbiph = biphenyltetramethylcyclopentadienyl, phpy = phenylpyridine, py = pyridine) unexpectedly reacts with the tripeptide glutathione in the presence of Coenzyme NADH to give glutathione sulfenate (Ir–S(O)G) and sulfinate (Ir–S(O)2G) complexes. These new adducts may play a role in the anticancer activity of such organoiridium complexes.
-
the potent oxidant anticancer activity of organoiridium catalysts
Angewandte Chemie, 2014Co-Authors: Zhe Liu, Abraha Habtemariam, Ana M Pizarro, Bushra Qamar, Isolda Romerocanelon, Jessica M Hearn, Nicolas P E Barry, Guy J Clarkson, Peter J SadlerAbstract:Platinum complexes are the most widely used anticancer drugs; however, new generations of agents are needed. The organoiridium(III) complex [(η5-Cpxbiph)Ir(phpy)(Cl)] (1-Cl), which contains π-bonded biphenyltetramethylcyclopentadienyl (Cpxbiph) and C^N-chelated phenylpyridine (phpy) ligands, undergoes rapid hydrolysis of the chlorido ligand. In contrast, the pyridine complex [(η5-Cpxbiph)Ir(phpy)(py)]+ (1-py) aquates slowly, and is more potent (in nanomolar amounts) than both 1-Cl and cisplatin towards a wide range of cancer cells. The pyridine ligand protects 1-py from rapid reaction with intracellular glutathione. The high potency of 1-py correlates with its ability to increase substantially the level of reactive oxygen species (ROS) in cancer cells. The unprecedented ability of these iridium complexes to generate H2O2 by catalytic hydride transfer from the Coenzyme NADH to oxygen is demonstrated. Such organoiridium complexes are promising as a new generation of anticancer drugs for effective oxidant therapy.
-
reduction of quinones by NADH catalyzed by organoiridium complexes
Angewandte Chemie, 2013Co-Authors: Zhe Liu, Robert J Deeth, Jennifer S Butler, Abraha Habtemariam, Mark E Newton, Peter J SadlerAbstract:One electron at a time: Half-sandwich organometallic cyclopentadienyl–IrIII complexes containing N,N-chelated ligands can catalyze the reduction of quinones (Q), such as vitamin K3, to semiquinones (Q.ˉ) by Coenzyme NADH (see picture). DFT calculations suggest that the mechanism involves hydride transfer followed by two one-electron transfers and the unusual IrII oxidation state as a key transient intermediate.
-
organometallic ruthenium and iridium transfer hydrogenation catalysts using Coenzyme NADH as a cofactor
Angewandte Chemie, 2012Co-Authors: Zhe Liu, Abraha Habtemariam, Soledad Betanzoslara, Ana M Pizarro, Bushra Qamar, Peter J SadlerAbstract:Artificial enzymes: half-sandwich arene ruthenium(II) and cyclopentadienyl iridium(III) complexes containing N,N-chelated ligands can use NADH as a source of hydride for the reduction of ketones. Moreover, cyclopentadienyl phenanthroline iridium(III) derivatives at micromolar concentrations are robust catalysts for the production of H(2) from NADH in water and can raise the NAD(+)/NADH ratio in cancer cells.
Ron S. Ronimus - One of the best experts on this subject based on the ideXlab platform.
-
Structural determination of archaeal UDP-N-acetylglucosamine 4-epimerase from Methanobrevibacter ruminantium M1 in complex with the bacterial cell wall intermediate UDP-N-acetylmuramic acid.
Proteins, 2018Co-Authors: Vincenzo Carbone, Linley R. Schofield, Carrie Sang, Andrew J. Sutherland-smith, Ron S. RonimusAbstract:The crystal structure of UDP-N-acetylglucosamine 4-epimerase (UDP-GlcNAc 4-epimerase; WbpP; EC 5.1.3.7), from the archaeal methanogen Methanobrevibacter ruminantium strain M1, was determined to a resolution of 1.65 A. The structure, with a single monomer in the crystallographic asymmetric unit, contained a conserved N-terminal Rossmann-fold for nucleotide binding and an active site positioned in the C-terminus. UDP-GlcNAc 4-epimerase is a member of the short-chain dehydrogenases/reductases superfamily, sharing sequence motifs and structural elements characteristic of this family of oxidoreductases and bacterial 4-epimerases. The protein was co-crystallized with Coenzyme NADH and UDP-N-acetylmuramic acid, the latter an unintended inclusion and well known product of the bacterial enzyme MurB and a critical intermediate for bacterial cell wall synthesis. This is a non-native UDP sugar amongst archaea and was most likely incorporated from the E. coli expression host during purification of the recombinant enzyme.
-
Structural determination of archaeal UDP-N-acetylglucosamine 4-epimerase from Methanobrevibacter ruminantium M1 in complex with the bacterial cell wall intermediate UDP-N-acetylmuramic acid
2018Co-Authors: Schofield L, Sang C, Sutherland-smith A, Ron S. RonimusAbstract:The crystal structure of UDP-N-acetylglucosamine 4-epimerase (UDP-GlcNAc 4-epimerase; WbpP; EC 5.1.3.7), from the archaeal methanogen Methanobrevibacter ruminantium strain M1, was determined to a resolution of 1.65 Å. The structure, with a single monomer in the crystallographic asymmetric unit, contained a conserved N-terminal Rossmann fold for nucleotide binding and an active site positioned in the C-terminus. UDP-GlcNAc 4-epimerase is a member of the short-chain dehydrogenase/reductase superfamily, sharing sequence motifs and structural elements characteristic of this family of oxidoreductases and bacterial 4-epimerases. The protein was co-crystallized with Coenzyme NADH and UDP-N-acetylmuramic acid, the latter an unintended inclusion and well known product of the bacterial enzyme MurB and a critical intermediate for bacterial cell wall synthesis. This is a non-native UDP sugar amongst archaea and was most likely incorporated from the Eschericha coli expression host during purification of the recombinant enzyme
-
Expression, Purification, and Characterization of (R)-Sulfolactate Dehydrogenase (ComC) from the Rumen Methanogen Methanobrevibacter millerae SM9
Archaea (Vancouver B.C.), 2017Co-Authors: Yanli Zhang, Linley R. Schofield, Carrie Sang, Debjit Dey, Ron S. RonimusAbstract:(R)-Sulfolactate dehydrogenase (EC 1.1.1.337), termed ComC, is a member of an NADH/NADPH-dependent oxidoreductase family of enzymes that catalyze the interconversion of 2-hydroxyacids into their corresponding 2-oxoacids. The ComC reaction is reversible and in the biosynthetic direction causes the conversion of (R)-sulfolactate to sulfopyruvate in the production of Coenzyme M (2-mercaptoethanesulfonic acid). Coenzyme M is an essential cofactor required for the production of methane by the methyl-Coenzyme M reductase complex. ComC catalyzes the third step in the first established biosynthetic pathway of Coenzyme M and is also involved in methanopterin biosynthesis. In this study, ComC from Methanobrevibacter millerae SM9 was cloned and expressed in Escherichia coli and biochemically characterized. Sulfopyruvate was the preferred substrate using the reduction reaction, with 31% activity seen for oxaloacetate and 0.2% seen for α-ketoglutarate. Optimal activity was observed at pH 6.5. The apparent KM for Coenzyme (NADH) was 55.1 μM, and for sulfopyruvate, it was 196 μM (for sulfopyruvate the Vmax was 93.9 μmol min−1 mg−1 and kcat was 62.8 s−1). The critical role of ComC in two separate cofactor pathways makes this enzyme a potential means of developing methanogen-specific inhibitors for controlling ruminant methane emissions which are increasingly being recognized as contributing to climate change.
Shunichi Fukuzumi - One of the best experts on this subject based on the ideXlab platform.
-
catalytic formation of hydrogen peroxide from Coenzyme NADH and dioxygen with a water soluble iridium complex and a ubiquinone Coenzyme analogue
Inorganic Chemistry, 2016Co-Authors: Tomoyoshi Suenobu, Satoshi Shibata, Shunichi FukuzumiAbstract:A ubiquinone Coenzyme analogue (Q0: 2,3-dimethoxy-5-methyl-1,4-benzoquinone) was reduced by Coenzyme NADH to yield the corresponding reduced form of Q0 (Q0H2) in the presence of a catalytic amount of a [C,N] cyclometalated organoiridium complex (1: [IrIII(Cp*)(4-(1H-pyrazol-1-yl-κN2)benzoic acid-κC3)(H2O)]2SO4) in water at ambient temperature as observed in the respiratory chain complex I (Complex I). In the catalytic cycle, the reduction of 1 by NADH produces the corresponding iridium hydride complex that in turn reduces Q0 to produce Q0H2. Q0H2 reduced dioxygen to yield hydrogen peroxide (H2O2) under slightly basic conditions. Catalytic generation of H2O2 was made possible in the reaction of O2 with NADH as the functional expression of NADH oxidase in white blood cells utilizing the redox cycle of Q0 as well as 1 for the first time in a nonenzymatic homogeneous reaction system.
Nirmala Ramanujam - One of the best experts on this subject based on the ideXlab platform.
-
metabolic mapping of mcf10a human breast cells via multiphoton fluorescence lifetime imaging of the Coenzyme NADH
Cancer Research, 2005Co-Authors: Damian K Bird, Kristin M Vrotsos, Kevin W Eliceiri, Emily M Vaughan, Patricia J Keely, John G White, Nirmala RamanujamAbstract:Biochemical estimation of NADH concentration is a useful method for monitoring cellular metabolism, because the NADH/NAD + reduction-oxidation pair is crucial for electron transfer in the mitochondrial electron chain. In this article, we present a novel method for deriving functional maps of intracellular reduction-oxidation ratio in vivo via measurement of the fluorescence lifetimes and the ratio of free and protein-bound NADH using two-photon fluorescence lifetime imaging (FLIM). Through systematic analysis of FLIM data from the control cells, it was observed that there is a statistically significant decrease in the fluorescence lifetime of both free and protein-bound NADH and the contribution of protein-bound NADH as cells progress from an early to logarithmic to confluent phase. Potassium cyanide (KCN) treatment and serum starvation of cells yielded similar changes. There was a statistically significant decrease in the fluorescence lifetime of protein-bound and free NADH at the early and logarithmic phase of the growth curve and a statistically significant decrease in the contribution of protein-bound NADH relative to that observed in the control cells at all three phases of the growth curve. The imposed perturbations (confluence, serum starvation, and KCN treatment) are all expected to result in an increase in the ratio of NADH/NAD + . Our studies suggest that the fluorescence lifetime of both the free and the protein-bound components of NADH and the ratio of free to protein-bound NADH is related to changes in the NADH/NAD + ratio.