Zinc complexes of chloroquine and hydroxychloroquine versus the mixtures of their components: Structures, solution equilibria/speciation and cellular zinc uptake.

The zinc complexes of chloroquine (CQ; [Zn(CQH)Cl]) and hydroxychloroquine (HO-CQ; [Zn(HO-CQH)Cl]) were synthesized and characterized by X-Ray structure analysis, FT-IR, NMR, UV-Vis spectroscopy, and cryo-spray mass spectrometry in solid state as well as in aqueous and organic solvent solutions, respectively. In acetonitrile, up to two Zn ions bind to CQ and HO-CQ through the tertiary amine and aromatic nitrogen atoms (K = (3.8 ± 0.

A macrocyclic quinol-containing ligand enables high catalase activity even with a redox-inactive metal at the expense of the ability to mimic superoxide dismutase.

Previously, we found that linear quinol-containing ligands could allow manganese complexes to act as functional mimics of superoxide dismutase (SOD). The redox activity of the quinol enables even Zn(ii) complexes with these ligands to catalyze superoxide degradation. As we were investigating the abilities of manganese and iron complexes with 1,8-bis(2,5-dihydroxybenzyl)-1,4,8,11-tetraazacyclotetradecane (Hqp4) to act as redox-responsive contrast agents for magnetic resonance imaging (MRI), we found evidence that they could also catalyze the dismutation of HO.

Reductive Coupling of Nitric Oxide by Cu(I): Stepwise Formation of Mono- and Dinitrosyl Species to a Cupric Hyponitrite Intermediate.

Transition-metal-mediated reductive coupling of nitric oxide (NO) to nitrous oxide (NO) has significance across the fields of industrial chemistry, biochemistry, medicine, and environmental health. Herein, we elucidate a density functional theory (DFT)-supplemented mechanism of NO reductive coupling at a copper-ion center, [(tmpa)Cu(MeCN)] () {tmpa = tris(2-pyridylmethyl)amine}. At -110 °C in EtOH (<-90 °C in MeOH), exposing to NO leads to a new binuclear hyponitrite intermediate [{(tmpa)Cu}(μ-NO)] (), exhibiting temperature-dependent irreversible isomerization to the previously characterized κ-O,O'--[(tmpa)Cu(μ-NO)] () complex.

Diquinol Functionality Boosts the Superoxide Dismutase Mimicry of a Zn(II) Complex with a Redox-Active Ligand while Maintaining Catalyst Stability and Enhanced Activity in Phosphate Solution.

In the current work, we demonstrate ligand design concepts that significantly improve the superoxide dismutase (SOD) activity of a zinc complex; the catalysis is enhanced when two quinol groups are present in the polydentate ligand. We investigate the mechanism through which the quinols influence the catalysis and determine the impact of entirely removing a chelating group from the original hexadentate ligand. Our results suggest that SOD mimicry with these compounds requires a ligand that coordinates Zn(II) strongly in both its oxidized and reduced forms and that the activity proceeds through Zn(II)-semiquinone complexes.

A Highly Water- and Air-Stable Iron-Containing MRI Contrast Agent Sensor for H O.

A highly water- and air-stable Fe(II) complex with the quinol-containing macrocyclic ligand H qp4 reacts with H O to yield Fe(III) complexes with less highly chelating forms of the ligand that have either one or two para-quinones. The reaction increases the T -weighted relaxivity over four-fold, enabling the complex to detect H O using clinical MRI technology. The iron-containing sensor differs from its recently characterized manganese analog, which also detects H O , in that it is the oxidation of the metal center, rather than the ligand, that primarily enhances the relaxivity.

Experimental and Computational Insight into the Mechanism of NO Binding to Ferric Microperoxidase. The Likely Role of Tautomerization to Account for the pH Dependence.

According to the current paradigm, the metal-hydroxo bond in a six-coordinate porphyrin complex is believed to be significantly less reactive in ligand substitution than the analogous metal-aqua bond, due to a much higher strength of the former bond. Here, we report kinetic studies for nitric oxide (NO) binding to a heme-protein model, acetylated microperoxidase-11 (AcMP-11), that challenge this paradigm. In the studied pH range 7.

Quinol-containing ligands enable high superoxide dismutase activity by modulating coordination number, charge, oxidation states and stability of manganese complexes throughout redox cycling.

Reactivity assays previously suggested that two quinol-containing MRI contrast agent sensors for HO, [Mn()(MeCN)] and [Mn()Br], could also catalytically degrade superoxide. Subsequently, [Zn()(OTf)] was found to use the redox activity of the ligand to catalyze the conversion of O˙ to O and HO, raising the possibility that the organic ligand, rather than the metal, could serve as the redox partner for O˙ in the manganese chemistry. Here, we use stopped-flow kinetics and cryospray-ionization mass spectrometry (CSI-MS) analysis of the direct reactions between the manganese-containing contrast agents and O˙ to confirm the activity and elucidate the catalytic mechanism.

A Macrocyclic Ligand Framework That Improves Both the Stability and -Weighted MRI Response of Quinol-Containing HO Sensors.

Previously prepared Mn(II)- and quinol-containing magnetic resonance imaging (MRI) contrast agent sensors for HO relied on linear polydentate ligands to keep the redox-activatable quinols in close proximity to the manganese. Although these provide positive -weighted relaxivity responses to HO that result from oxidation of the quinol groups to -quinones, these reactions weaken the binding affinity of the ligands, promoting dissociation of Mn(II) from the contrast agent in aqueous solution. Here, we report a new ligand, 1,8-bis(2,5-dihydroxybenzyl)-1,4,8,11-tetraazacyclotetradecane, that consists of two quinols covalently tethered to a cyclam macrocycle.

A broad view on the complexity involved in water oxidation catalysis based on Ru-bpn complexes.

A new Ru complex with the formula [Ru(bpn)(pic)]Cl (where bpn is 2,2'-bi(1,10-phenanthroline) and pic stands for 4-picoline) (1Cl) is synthesized to investigate the true nature of active species involved in the electrochemical and chemical water oxidation mediated by a class of N4 tetradentate equatorial ligands. Comprehensive electrochemical (by using cyclic voltammetry, differential pulse voltammetry, and controlled potential electrolysis), structural (X-ray diffraction analysis), spectroscopic (UV-vis, NMR, and resonance Raman), and kinetic studies are performed. 1 undergoes a substitution reaction when it is chemically (by using NaIO) or electrochemically oxidized to Ru, in which picoline is replaced by an hydroxido ligand to produce [Ru(bpn)(pic)(OH)] (2).

Selectivity of tungsten mediated dinitrogen splitting proton reduction.

Mo complexes are currently the most active catalysts for nitrogen fixation under ambient conditions. In comparison, tungsten platforms are scarcely examined. For active catalysts, the control of N proton reduction selectivities remains a difficult task.

Positive Charge on Porphyrin Ligand and Nature of Metal Center Define Basic Physicochemical Properties of Cationic Manganese and Iron Porphyrins in Aqueous Solution.

Recently, comprehensive studies on positively charged manganese porphyrins show that these compounds, known for their superoxide dismutase (SOD) mimetic ability, can be equally reactive toward a broad array of other redox active molecules of biological relevance present in a cellular milieu. In this context, the examination of some fundamental aspects of physicochemical behavior of metalloporphyrins behind their rich aqueous chemistry is believed to provide a valuable basis for the understanding of newly observed biological effects of these compounds in vivo and throw more light on a potential use of common SOD porphyrin mimetics for other redox active cellular targets in order to earn desirable therapeutic effects. Herein, we present versatile characteristics of highly positively charged Mn(P) and Fe(P) porphyrins (with up to +9 and +8 overall charge, respectively) with regard to their acid-base equilibria, metal coordination sphere, water-exchange dynamics, redox properties, and substitution behavior toward selected ligands.

Formation and Reactivity of New Isoporphyrins: Implications for Understanding the Tyr-His Cross-Link Cofactor Biogenesis in Cytochrome Oxidase.

Cytochrome oxidase (CO) catalyzes the reduction of dioxygen to water utilizing a heterobinuclear active site composed of a heme moiety and a mononuclear copper center coordinated to three histidine residues, one of which is covalently cross-linked to a tyrosine residue via a post-translational modification (PTM). Although this tyrosine-histidine moiety has functional and structural importance, the pathway behind this net oxidative C-N bond coupling is still unknown. A novel route employing an iron(III) -substituted isoporphyrin derivative, isoelectronic with Cmpd-I ((Por)Fe═O), is for the first time proposed to be a key intermediate in the Tyr-His cofactor biogenesis.

Two Unsupported Terminal Hydroxido Ligands in a μ-Oxo-Bridged Ferric Dimer: Protonation and Kinetic Lability Studies.

The dinuclear complex [(susan){Fe(OH)(μ-O)Fe(OH)}](ClO) (Fe(OH)(ClO); susan = 4,7-dimethyl-1,1,10,10-tetra(2-pyridylmethyl)-1,4,7,10-tetraazadecane) with two unsupported terminal hydroxido ligands and for comparison the fluorido-substituted complex [(susan){FeF(μ-O)FeF}](ClO) (FeF(ClO)) have been synthesized and characterized in the solid state as well in acetonitrile (CHCN) and water (HO) solutions. The Fe-OH bonds are strongly modulated by intermolecular hydrogen bonds (1.85 and 1.

Structure and reactivity of [Ru(terpy)(N^N)Cl]Cl complexes: consequences for biological applications.

The crystal structures of [Ru(terpy)(bipy)Cl]Cl·2HO and [Ru(terpy)(en)Cl]Cl·3HO, where terpy = 2,2':6',2''-terpyridine, bipy = 2,2'-bipyridine and en = ethylenediamine, were determined and compared to the structure of the complexes in solution obtained by multi-nuclear NMR spectroscopy in DMSO as a solvent. In aqueous solution, both chlorido complexes aquate fully to the corresponding aqua complexes, viz. [Ru(terpy)(bipy)(HO)] and [Ru(terpy)(en)(HO)], within ca.

Switching between Inner- and Outer-Sphere PCET Mechanisms of Small-Molecule Activation: Superoxide Dismutation and Oxygen/Superoxide Reduction Reactivity Deriving from the Same Manganese Complex.

Readily exchangeable water molecules are commonly found in the active sites of oxidoreductases, yet the overwhelming majority of studies on small-molecule mimics of these enzymes entirely ignores the contribution of water to the reactivity. Studies of how these enzymes can continue to function in spite of the presence of highly oxidizing species are likewise limited. The mononuclear Mn complex with the potentially hexadentate ligand N-(2-hydroxy-5-methylbenzyl)-N,N',N'-tris(2-pyridinylmethyl)-1,2-ethanediamine (L) was previously found to act as both a HO-responsive MRI contrast agent and a mimic of superoxide dismutase (SOD).

Spectroscopic and Kinetic Evidence for the Crucial Role of Compound 0 in the P450cam -Catalyzed Hydroxylation of Camphor by Hydrogen Peroxide.

The hydroperoxo iron(III) intermediate P450cam Fe(III) -OOH, being the true Compound 0 (Cpd 0) involved in the natural catalytic cycle of P450cam , could be transiently observed in the peroxo-shunt oxidation of the substrate-free enzyme by hydrogen peroxide under mild basic conditions and low temperature. The prolonged lifetime of Cpd 0 enabled us to kinetically examine the formation and reactivity of P450cam Fe(III) -OOH species as a function of varying reaction conditions, such as pH, and concentration of H2 O2 , camphor, and potassium ions. The mechanism of hydrogen peroxide binding to the substrate-free form of P450cam differs completely from that observed for other heme proteins possessing the distal histidine as a general acid-base catalyst and is mainly governed by the ability of H2 O2 to undergo deprotonation at the hydroxo ligand coordinated to the iron(III) center under conditions of pH≥p${K{{{\rm P450}\hfill \atop {\rm a}\hfill}}}$.

Drug metabolism by cytochrome p450 enzymes: what distinguishes the pathways leading to substrate hydroxylation over desaturation?

Cytochrome P450 enzymes are highly versatile biological catalysts in our body that react with a broad range of substrates. Key functions in the liver include the metabolism of drugs and xenobiotics. One particular metabolic pathway that is poorly understood relates to the P450 activation of aliphatic groups leading to either hydroxylation or desaturation pathways.

Direct evidence for catalase activity of [Ru(V)(edta)(O)](-).

Reported is the first example of a ruthenium(III) complex, Ru(III)(edta) (edta(4-) = ethylenediaminetetraacetate), that catalyzes the disproportion of H2O2 to O2 and water in resemblance to catalase activity, and shedding light on the possible mechanism of action of the [Ru(V)(edta)(O)](-) formed in the reacting system.

Combined experimental and theoretical study on the reactivity of compounds I and II in horseradish peroxidase biomimetics.

For the exploration of the intrinsic reactivity of two key active species in the catalytic cycle of horseradish peroxidase (HRP), Compound I (HRP-I) and Compound II (HRP-II), we generated in situ [Fe(IV) O(TMP(+.) )(2-MeIm)](+) and [Fe(IV) O(TMP)(2-MeIm)](0) (TMP=5,10,15,20-tetramesitylporphyrin; 2-MeIm=2-methylimidazole) as biomimetics for HRP-I and HRP-II, respectively. Their catalytic activities in epoxidation, hydrogen abstraction, and heteroatom oxidation reactions were studied in acetonitrile at -15 °C by utilizing rapid-scan UV/Vis spectroscopy.

Mechanistic insight into peroxo-shunt formation of biomimetic models for compound II, their reactivity toward organic substrates, and the influence of N-methylimidazole axial ligation.

High-valent iron-oxo species have been invoked as reactive intermediates in catalytic cycles of heme and nonheme enzymes. The studies presented herein are devoted to the formation of compound II model complexes, with the application of a water soluble (TMPS)Fe(III)(OH) porphyrin ([meso-tetrakis(2,4,6-trimethyl-3-sulfonatophenyl)porphinato]iron(III) hydroxide) and hydrogen peroxide as oxidant, and their reactivity toward selected organic substrates. The kinetics of the reaction of H2O2 with (TMPS)Fe(III)(OH) was studied as a function of temperature and pressure.

Temperature and pressure effects on C-H abstraction reactions involving compound I and II mimics in aqueous solution.

The presented results cover a comparative mechanistic study on the reactivity of compound (Cpd) I and II mimics of a water-soluble iron(III) porphyrin, [meso-tetrakis(2,4,6-trimethyl-3-sulfonatophenyl)porphinato]iron(III), Fe(III)(TMPS). The acidity of the aqueous medium strongly controls the chemical nature and stability of the high-valent iron(IV) oxo species. Reactivity studies were performed at pH 5 and 10, where the Cpd I and II mimics are stabilized as the sole oxidizing species, respectively.

Ru(III)(edta) mediated oxidation of azide in the presence of hydrogen peroxide. Azide versus peroxide activation.

The [Ru(III)(edta)(H2O)](-) (edta(4-) = ethylenediaminetetraacetate) complex catalyzes the oxidation of azide (N3(-)) with H2O2, mimicking the action of metallo-enzymes such as catalase and peroxidase in biochemistry. The kinetics of the catalytic oxidation process was studied by using stopped-flow and rapid-scan spectrophotometry as a function of [Ru(III)(edta)], [H2O2], [N3(-)] and pH. The catalytic activity of the different oxidizing species produced in the reaction of [Ru(III)(edta)(H2O)](-) with H2O2 for the oxidation of azide was compared to the oxidation of coordinated azide in [Ru(III)(edta)N3](2-) by H2O2.

A complete volume profile for the reversible binding of camphor to cytochrome P450(cam).

The effect of pressure on the kinetics and thermodynamics of the reversible binding of camphor to cytochrome P450(cam) was studied as a function of the K(+) concentration. The determination of the reaction and activation volumes enabled the construction of the first complete volume profile for the reversible binding of camphor to P450(cam). Although the volume profiles constructed for the reactions conducted at low and high K(+) concentrations are rather similar, and both show a drastic volume increase on going from the reactant to the transition state and a relatively small volume change on going from the transition to the product state, the position of the transition state is largely affected by the K(+) concentration in solution.