Superoxide Dismutase-like Activity of Zeolitic Imidazolate Framework Nanoparticles Comprising Biomimetic Imidazolato-bridged CuZn Units.

Nanoparticles exhibiting enzymatic functions have garnered considerable attention due to their structural robustness and the profusion of active sites that can be introduced to a single nanosized particle. Here we report that nanosized mixed-metal zeolitic imidazolate frameworks (ZIFs) show a superoxide dismutase (SOD)-like catalytic activity. We chose a ZIF composed of copper and zinc ions and 2-methylimidazole, CuZn-ZIF-8, in which the Cu and Zn ions are bridged by an imidazolato ligand. This coordination geometry closely mimics the active site of CuZn superoxide dismutase (CuZnSOD). The CuZn-ZIF-8 nanoparticles exhibit potent SOD-like activity, attributed to their porous nature and numerous copper active sites, and also possess exceptional recyclability.

Electrochemical Epoxidation Catalyzed by Manganese Salen Complex and Carbonate with Boron-Doped Diamond Electrode.

Epoxides are essential precursors for epoxy resins and other chemical products. In this study, we investigated whether electrochemically oxidizing carbonate ions could produce percarbonate to promote an epoxidation reaction in the presence of appropriate metal catalysts, although Tanaka and co-workers had already completed a separate study in which the electrochemical oxidation of chloride ions was used to produce hypochlorite ions for electrochemical epoxidation. We found that epoxides could be obtained from styrene derivatives in the presence of metal complexes, including manganese(III) and oxidovanadium(IV) porphyrin complexes and manganese salen complexes, using a boron-doped diamond as the anode. After considering various complexes as potential catalysts, we found that manganese salen complexes showed better performance in terms of epoxide yield. Furthermore, the substituent effect of the manganese salen complex was also investigated, and it was found that the highest epoxide yields were obtained when Jacobsen's catalyst was used. Although there is still room for improving the yields, this study has shown that the in situ electrochemical generation of percarbonate ions is a promising method for the electrochemical epoxidation of alkenes.

Dicopper(II) Complexes of p-Cresol-2,6-Bis(dpa) Amide-Tether Ligands: Large Enhancement of Oxidative DNA Cleavage, Cytotoxicity, and Mechanistic Insight by Intracellular Visualization.

Dicopper complexes of a new p-cresol-2,6-bis(dpa) amide-tether ligand (HL1), [Cu2(µ-OH2)(µ-1,3-OAc)(L1)](ClO4)2 (1) and [Cu2(µ-1,1-OAc)(µ-1,3-OAc)(L1)]X (X = ClO4 (2a), OAc (2b)) were synthesized and structurally characterized. 2b rapidly cleaves supercoiled plasmid DNA by activating H2O2 at neutral pH to a linear DNA and shows remarkable cytotoxicity in comparison with related complexes. As 2b is more cytotoxic than HL1, the dicopper core is kept in the cell. A boron dipyrromethene (Bodipy)-modified complex of the p-cresol-2,6-bis(dpa) amide-tether ligand having a Bodipy pendant (HL2), [Cu2(µ-OAc)2(L2)](OAc) (3), was synthesized to visualize intracellular behavior, suggesting that 2b attacks the nucleolus and mitochondria. A comet assay clearly shows that 2b does not cleave nuclear DNA. The apoptotic cell death is evidenced from flow cytometry.

Oxidative DNA Cleavage, Formation of µ-1,1-Hydroperoxo Species, and Cytotoxicity of Dicopper(II) Complex Supported by a p-Cresol-Derived Amide-Tether Ligand.

Metal complexes to promote oxidative DNA cleavage by H2O2 are desirable as anticancer drugs. A dicopper(II) complex of known p-cresol-derived methylene-tether ligand Hbcc [Cu2(bcc)]3+ did not promote DNA cleavage by H2O2. Here, we synthesized a new p-cresol-derived amide-tether one, 2,6-bis(1,4,7,10-tetrazacyclododecyl-1-carboxyamide)-p-cresol (Hbcamide). A dicopper(II) complex of the new ligand [Cu2(µ-OH)(bcamide)]2+ was structurally characterized. This complex promoted the oxidative cleavage of supercoiled plasmid pUC19 DNA (Form I) with H2O2 at pH 6.0-8.2 to give Forms II and III. The reaction was largely accelerated in a high pH region. A µ-1,1-hydroperoxo species was formed as the active species and spectroscopically identified. The amide-tether complex is more effective in cytotoxicity against HeLa cells than the methylene-tether one.

Hydrogen Peroxide-Reducing Factor Released by PC12D Cells Increases Cell Tolerance against Oxidative Stress.

PC12D cells, a subline of rat adrenal pheochromocytoma PC12 cells, extend neurites rapidly in response to differentiation stimuli and are used to investigate the molecular mechanisms of neurite extension. In the present study, we found significant tolerance of PC12D cells against Parkinson's disease-related stimuli such as dopamine and 6-hydroxydopamine; this tolerance was significantly decreased by a change in the medium. Conditioned medium from PC12D cells induced tolerance against oxidative stress, which suggests that cytoprotective factor may be released by PC12D cells into the culture medium. Conditioned medium-induced tolerance was not found for PC12 cells or human neuroblastoma SH-SY5Y cells. A cytoprotective factor generated by PC12D cells exhibited hydrogen peroxide-reducing activity. Chemical characterization showed that this cytoprotective factor is water soluble and has a molecular weight about 1000 Da, and that its activity is inhibited by sodium cyanide. Release of this cytoprotective factor was increased by differentiation stimuli and oxidative stress. Taken together, these results suggest that release of a hydrogen peroxide-reducing factor by PC12D cells increases cell tolerance against oxidative stress. This study provides new insights into the antioxidative properties of factors in extracellular fluid.

Specific Enhancement of Catalytic Activity by a Dicopper Core: Selective Hydroxylation of Benzene to Phenol with Hydrogen Peroxide.

A dicopper(II) complex, stabilized by the bis(tpa) ligand 1,2-bis[2-[bis(2-pyridylmethyl)aminomethyl]-6-pyridyl]ethane (6-hpa), [Cu2 (µ-OH)(6-hpa)]3+ , was synthesized and structurally characterized. This complex catalyzed selective hydroxylation of benzene to phenol using H2 O2 , thus attaining large turnover numbers (TONs) and high H2 O2 efficiency. The TON after 40 hours for the phenol production exceeded 12000 in MeCN at 50 °C under N2 , the highest value reported for benzene hydroxylation with H2 O2 catalyzed by homogeneous complexes. At 22 % benzene conversion, phenol (95.2 %) and p-benzoquinone (4.8 %) were produced. The mechanism of H2 O2 activation and benzene hydroxylation is proposed.

Formation and High Reactivity of the anti-Dioxo Form of High-Spin µ-Oxodioxodiiron(IV) as the Active Species That Cleaves Strong C-H Bonds.

Recently, it was shown that µ-oxo-µ-peroxodiiron(III) is converted to high-spin µ-oxodioxodiiron(IV) through O-O bond scission. Herein, the formation and high reactivity of the anti-dioxo form of high-spin µ-oxodioxodiiron(IV) as the active oxidant are demonstrated on the basis of resonance Raman and electronic-absorption spectral changes, detailed kinetic studies, DFT calculations, activation parameters, kinetic isotope effects (KIE), and catalytic oxidation of alkanes. Decay of µ-oxodioxodiiron(IV) was greatly accelerated on addition of substrate. The reactivity order of substrates is toluene

Nucleophilic ring opening of meso-substituted 5-oxaporphyrin by oxygen, nitrogen, sulfur, and carbon nucleophiles.

Nucleophilic ring opening of 23H-[21,23-didehydro-10,15,20-tris(4-methoxycarbonylphenyl)-5-oxaporphyrinato](trifluoroacetato)zinc(II) with various nucleophiles such as alkoxide, amine, thiolate, and enolate gave 19-substituted bilinone zinc complexes, and they were isolated as free base bilinones. An X-ray crystallographic study demonstrated that the product of 5-oxaporphyrin with sodium methoxide was 21H,23H-(4Z,9Z,15Z)-1,21-dihydro-19-methoxy-5,10,15-tris(4-methoxycarbonylphenyl)bilin-1-one with a helicoidal conformation. The structure of the product of 5-oxaporphyrin with an enolate of ethyl acetoacetate was 21H,22H,24H-(4Z,9Z,15Z,19E)-19-(1-ethoxycarbonyl-2-oxopropylidene)-5,10,15-tris(4-methoxycarbonylphenyl)-1,19,21,24-tetrahydrobilin-1-one, with three inner NH groups. The product with SH(-) was also the same tautomer, 21H,22H,24H-19-thioxo-bilin-1-one, with three NH groups, while the products with RO(-), RNH2, and RS(-) nucleophiles were 21H,23H-bilin-1-ones with two inner NH groups. The first-order rate constants of the ring opening reaction of 5-oxaporphyrin with 1 M BnOH and BnSH in toluene at 303 K were 3.0 × 10(-4) and 6.1 × 10(-4) s(-1), respectively. The ratio of the rate of alcohol to thiol was much higher than that with methyl iodide, suggesting that 5-oxaporphyrin reacted as a hard electrophile in comparison to methyl iodide. UV-visible spectra of 19-substituted bilinones in CHCl3 at 298 K showed that the absorption maximum of the lower energy band was red-shifted in increasing order of O-substituted (645 nm), S-substituted (668 nm), N-substituted (699 nm), and C-substituted bilinones (706 nm).

Electronic tuning of iron-oxo-mediated C-H activation: effect of electron-donating ligand on selectivity.

We have reported previously that an iron(III) complex supported by an anionic pentadentate monoamido ligand, dpaq(H) (dpaq(H) =2-[bis(pyridin-2-ylmethyl)]amino-N-quinolin-8-yl-acetamido), promotes selective CH hydroxylation with H2 O2 with high regioselectivity. Herein, we report on the preparation of Fe(III) -dpaq derivatives that have a series of substituent groups at the 5-position of a quinoline moiety in the parent ligand dpaq(H) (dpaq(R) , R: OMe, H, Cl, and NO2 ), and examine them with respect to their catalytic activity in CH hydroxylation with H2 O2 . As the substituent group becomes more electron-withdrawing, both the selectivity and the turnover number increase, but the selectivity of epoxidation shows the opposite trend.

Roles of DNA Target in Cancer Cell-Selective Cytotoxicity by Dicopper Complexes with DNA Target/Ligand Conjugates.

The DNA target/ligand conjugates (HLX, X = Pn and Mn, n = 1-3) were synthesized where various lengths of -CONH(CH2CH2O)nCH2CH2NHCO- linkers with a 9-phenanthrenyl (P) or methyl (M) terminal as DNA targets replace the methyl group of 2,6-di(amide-tether cyclen)-p-cresol ligand (HL). DNA binding, DNA cleavage, cellular uptake, and cytotoxicity of [Cu2(µ-OH)(LX)](ClO4)2 (1X) are examined and compared with those of [Cu2(µ-OH)(L)](ClO4)2 (1) to clarify roles of DNA targets. Upon reaction of 1X with H2O2, µ-1,1-O2H complexes are formed for DNA cleavage. 1P1, 1P2, and 1P3 are 22-, 11-, 3-fold more active for conversion of Form II to III in the cleavage of supercoiled plasmid DNA with H2O2 than 1, where the short P-linker may fix a dicopper moiety within a small number of base pairs to facilitate DNA double-strand breaks (dsb). This enhances the proapoptotic activity of 1P1, 1P2, and 1P3, which are 30-, 12-, and 9.9-fold cytotoxic against HeLa cells than 1. DNA dsb and cytotoxicity are 44% correlated in 1P1-3 but 5% in 1M1-3, suggesting specific DNA binding of P-linkers and nonspecific binding of M-linkers in biological cells. 1P1-3 exert cancer cell-selective cytotoxicity against lung and pancreas cancer and normal cells where the short P-linker enhances the selectivity, but 1M1-3 do not. Intracellular visualization, apoptosis assay, and caspase activity assay clarify mitochondrial apoptosis caused by 1P1-3. The highest cancer cell selectivity of 1P1 may be enabled by the short P-linker promoting dsb of mitochondrial DNA with H2O2 increased by mitochondrial dysfunction in cancer cells.

Stacking of a Cofacially Stacked Iron Phthalocyanine Dimer on Graphite Achieved High Catalytic CH4 Oxidation Activity Comparable to That of pMMO.

Numerous biomimetic molecular catalysts inspired by methane monooxygenases (MMOs) that utilize iron or copper-oxo species as key intermediates have been developed. However, the catalytic methane oxidation activities of biomimetic molecule-based catalysts are still much lower than those of MMOs. Herein, we report that the close stacking of a µ-nitrido-bridged iron phthalocyanine dimer onto a graphite surface is effective in achieving high catalytic methane oxidation activity. The activity is almost 50 times higher than that of other potent molecule-based methane oxidation catalysts and comparable to those of certain MMOs, in an aqueous solution containing H2O2. It was demonstrated that the graphite-supported µ-nitrido-bridged iron phthalocyanine dimer oxidized methane, even at room temperature. Electrochemical investigation and density functional theory calculations suggested that the stacking of the catalyst onto graphite induced partial charge transfer from the reactive oxo species of the µ-nitrido-bridged iron phthalocyanine dimer and significantly lowered the singly occupied molecular orbital level, thereby facilitating electron transfer from methane to the catalyst in the proton-coupled electron-transfer process. The cofacially stacked structure is advantageous for stable adhesion of the catalyst molecule on the graphite surface in the oxidative reaction condition and for preventing decreases in the oxo-basicity and generation rate of the terminal iron-oxo species. We also demonstrated that the graphite-supported catalyst exhibited appreciably enhanced activity under photoirradiation owing to the photothermal effect.

Reversible O-O bond scission of peroxodiiron(III) to high-spin oxodiiron(IV) in dioxygen activation of a diiron center with a bis-tpa dinucleating ligand as a soluble methane monooxygenase model.

The conversion of peroxodiiron(III) to high-spin S = 2 oxodiiron(IV) via reversible O-O bond scission in a diiron complex with a bis-tpa dinucleating ligand, 6-hpa, has been characterized by elemental analysis; kinetic measurements for alkene epoxidation; cold-spray ionization mass spectrometry; and electronic absorption, Mössbauer, and resonance Raman spectroscopy to gain insight into the O(2) activation mechanism of soluble methane monooxygenases. This is the first synthetic example of a high-spin S = 2 oxodiiron(IV) species that oxidizes alkenes to epoxides efficiently. The bistability of the peroxodiiron(III) and high-spin S = 2 oxodiiron(IV) moieties is the key feature for the reversible O-O bond scission.

Synthesis, reactivity, and spectroscopic properties of meso-triaryl-5-oxaporphyrins.

[meso-Triaryl-21,23-didehydro-23H-5-oxaporphyrinato](trifluoroacetato)zinc(II) was prepared by the reaction of meso-triarylbilindione with acetic anhydride and zinc acetate, and it was isolated as a trifluoroacetate salt. The X-ray crystallographic study demonstrated that the trifluoroacetate anion was coordinated to the zinc ion. [21,23-Didehydro-10,15,20-tris(4-methoxycarbonylphenyl)-23H-5-oxaporphyrinato](trifluoroacetato)zinc(II) 3a was dissolved in various organic solvents such as toluene, chloroform, diethyl ether, ethyl acetate, acetone, acetonitrile, methanol, DMSO, and DMF, although it readily reacted with alcohols and DMF to yield linear tetrapyrroles. The solubility of 3a in toluene was 4.2 ± 0.1 g dm(-3) at room temperature. 3a showed characteristic UV-vis absorption at 649 nm and fluorescence emission at 657 nm in chloroform. The fluorescence quantum yields of 3a, [21,23-didehydro-10,15,20-triphenyl-23H-5-oxaporphyrinato](trifluoroacetato)zinc(II) (3c), and [21,23-didehydro-10,15,20-tris(4-methoxyphenyl)-23H-5-oxaporphyrinato](trifluoroacetato)zinc(II) (3b) were 0.071, 0.071, and 0.050, respectively. Reaction of 3a with EtOH afforded the zinc complex of 19-ethoxybilinone, and it proceeded 2 orders of magnitude faster than that of [ß-octaalkyl-21,23-didehydro-23H-5-oxaporphyrinato]zinc(II). The reaction with alcohols was sensitive to steric bulk of the alcohols; the rate of reaction with i-PrOH was 2700 times faster than that of t-BuOH at 303 K. The reaction of [meso-triaryl-21,23-didehydro-23H-5-oxaporphyrinato]zinc(II) with water proceeded 3 orders of magnitude slower than that with EtOH.

An iron(III)-monoamidate complex catalyst for selective hydroxylation of alkane C-H bonds with hydrogen peroxide.

Selective oxidation: the success of the title reaction is caused by the strong electron donation from the amidate moiety of the dpaq ligand to the iron center (dpaq=2-[bis(pyridin-2-ylmethyl)]amino-N-quinolin-8-yl-acetamidate). This process facilitates the O-O bond heterolysis of the intermediate Fe(III)OOH species to generate a selective oxidant without forming highly reactive hydroxyl radicals.

Enhancement of cancer-cell-selective cytotoxicity by a dicopper complex with a phenanthrene amide-tether ligand conjugate via mitochondrial apoptosis.

Dicopper complexes [Cu2(µ-OH)(Ln)](ClO4)2 [n = 1 (1) and 2 (2)] with a novel phenanthrene amide-tether ligand conjugate (HL1) and the original p-cresol-2,6-bis(amidecyclen) (HL2) were synthesized. A phenanthrene unit of 1 enhances the DNA-binding by 9-fold, enabling 1 to convert supercoiled plasmid DNA with H2O2 to a linear one in a 9.3-fold higher yield than 2. 1 reacts with H2O2 to form the µ-1,1-hydroperoxodicopper(II) complex 3 as the active species. The IC50 values of 1 against cancer cells of the lung and pancreas are 23.8 and 18.4 µM, respectively, 12-fold more toxic than the 284 and 241 µM of 2. Confocal microscopy, fluorescence-activated cell sorting, and caspase activity assays using HeLa cells revealed that 1 induces mitochondrial apoptosis. A DNA-targeting phenanthrene unit of 1 enhances the cancer-cell-selective toxicity via mitochondrial apoptosis.

Detection of enzymatically generated hydrogen peroxide by metal-based fluorescent probe.

We developed a metal-based fluorescent probe for H(2)O(2) called MBFh1, which has an iron complex as a reaction site for H(2)O(2) and a 3,7-dihydroxyphenoxazine derivative as the fluorescent reporter unit. The iron complex reacts quickly with H(2)O(2) to form oxidants, and then the oxidants convert the closely appended nonfluorescent 3,7-dihydroxyphenoxazine moiety to resorufin in an intramolecular fashion. The quick response to H(2)O(2) allows us to plot the enzymatic evolution of H(2)O(2). A combination of N-acetyl-3,7-dihydroxyphenoxazine and horseradish peroxidase has been frequently used to detect enzymatically generated H(2)O(2), but this method has interference with phenol derivatives. The use of MBFh1 overcomes this drawback.

An in situ quick XAFS spectroscopy study on the formation mechanism of small gold nanoparticles supported by porphyrin-cored tetradentate passivants.

We previously reported that a porphyrin-cored tetradentate passivant, which has two disulfide straps over one face of the porphyrin plane, can produce monolayer-protected gold nanoparticles, 2-4 nm in size, by the one-pot reduction of HAuCl(4) in DMF. The resulting nanoparticles are smaller than those prepared using the same S/Au molar ratio of a monodentate passivant. To examine the formation mechanism of small gold nanoparticles, the formation of gold nanoparticles in the presence of porphyrin-cored tetradentate passivants or a structurally related monodentate passivant was studied by time-resolved quick X-ray absorption fine structure spectroscopy. The results demonstrated that all of Au ions in solution are reduced to compose small Au clusters, i.e. nuclei, just after the NaBH(4) reduction of HAuCl(4) in both cases, but their size varied with the initial S/Au molar ratios and structure of the passivants. Thus, the size of Au nuclei was kinetically controlled by the passivants. Interestingly, the porphyrin-cored tetradentate passivant could stabilize smaller gold nanoparticles, 2-4 nm in size, but it was less efficient in trapping the Au nuclei formed at a very early stage, in comparison to the monodentate passivant.

π Back-bonding of iron(II) complexes supported by tris(pyrid-2-ylmethyl)amine and its nitro-substituted derivatives.

The electronic and geometric structures of a series of iron(II) complexes supported by tetradentate tris(pyrid-2-ylmethyl)amine-type ligands with different numbers of 4-nitropyridine groups, [(PyCH(2))(3-n)(4-NO(2)PyCH(2))(n)N] (n = 0-3), were examined by X-ray absorption fine-structure and variable-temperature (1)H NMR spectroscopies and theoretical calculations to reveal how the low-spin state is stabilized through π back-bonding interactions between iron(II) and 4-nitropyridine donor group(s).

Synthesis and characterization of a binuclear iron(III) complex bridged by 1-aminocyclopropane-1-carboxylic acid. Ethylene production in the presence of hydrogen peroxide.

A mu-oxo-diiron(III) complex bridged by two molecules of 1-aminocyclopropane-1-carboxylic acid (ACCH) was prepared with the ligand 1,4,7-triazacyclononane (TACN): [(TACN)Fe(2)(mu-O)(mu-ACCH)(2)](ClO(4))(4) x 2 H(2)O (1). This complex was characterized, and its crystal structure was solved. The bridging amino acid moieties were found in their zwitterionic forms (noted as ACCH). Reactivity assays were performed in the presence of hydrogen peroxide, and 1 turned out to be the first example of a well-characterized iron-ACCH complex able to produce ethylene from the bound ACCH moiety. The reaction requires the presence of a few equivalents of base, probably involved in the deprotonation of the amine groups of the ACCH bridges.

One-phase synthesis of small gold nanoparticles coated by a horizontal porphyrin monolayer.

One-pot reduction of HAuCl4 in a DMF solution containing a porphyrin-cored tetradentate passivant gives horizontal porphyrin monolayer-coated gold nanoparticles, whose particle size is significantly smaller than that made by using monodentate passivants under identical conditions.