High-valent transition metal centers and noninnocent ligands in metalloporphyrins and related molecules: a broad overview based on quantum chemical calculations

Using density functional theory, we have carried out a quantum chemical survey of high-valent transition metal porphyrins and related compounds. Discussed herein are recent developments on metalloporphyrin pi-cation radicals, high-valent manganese and iron porphyrins and heme protein intermediates, nickel(III) porphyrinoids, coenzyme F430, and high-valent transition metal corroles. In particular, we focus on whether the molecules of interest feature "true" high-valent metal centers, whether the ligands are oxidized instead, i.e. are noninnocent, or whether the electronic structures fall somewhere along the continuum between these scenarios.     

High-valent intermediates of heme proteins and model compounds

Recent computational and experimental probes of high-valent intermediates in heme proteins and model compounds reveal a rich spectrum of chemical behavior that is dependent on the nature of the proximal ligand, metal center, distal- and proximal-binding site environment, porphyrin macrocycle architecture, and consequent electronic structure. The results of such studies reveal an underlying complexity, which is simply understood once one is cognizant of the 'chameleon'-like behavior of such intermediates is determined by the high-valent intermediate environment.     

Spontaneous nucleophilic addition of hydroxide ions to the meso-position of high-valent antimony-oxo porphyrin complexes

Bimolecular reactions of the antimony(V) porphyrin complexes SbO(tpp)OH, 1 and SbO(oep)OH, 2 with tetra-n-butylammonium hydroxide were investigated at 298 K in acetonitrile solution (tpp, dianion of 5,10,15,20-tetraphenylporphyrin and oep, dianion of 2,3,7,8,12,13,17,18-octaethylporphyrin). Spontaneous nucleophilic addition of hydroxide ions to the non-oxidized porphyrin macrocycle leads to novel hydroxyphlorin derivatives, which contain a saturated meso-carbon bridge. While this process is a reversible equilibrium reaction for the TPP derivative, the OEP complex undergoes subsequent demetallation and oxidative ring cleavage in the presence of dioxygen. Possible implications for the competitive inhibition of heme-oxygenase by high-valent metalloporphyrin therapeutics are discussed.     

Rate-limiting step of the iron porphyrin-catalysed oxidation of cyclohexane to adipic acid by DFT method

Deep understanding of the rate-limiting step in the oxidation process of cyclohexane to adipic acid would be useful for improving the activity of catalysts and selectivity of goal products. The rate-limiting step lied in high-valent species generation or C–H bond oxidation remains a controversial topic. In this paper, the mechanism of high-valent species generation and C–H bond activation was investigated by density functional theory. It was observed that the activation barrier of the high-valent species was lower than that of C–H bond activation; thereby the C–H bond oxidation was determined as the rate-limiting step. Calculated geometries and energies were in close agreement with the experimental observations. Furthermore, frontier molecular orbital analysis revealed that the C–H bond interacted with the high-valent species in different orientation and it showed how the reaction was manipulated and controlled by the iron–porphyrin in the catalytic process. Given the calculation correction, experiments were designed to reveal the rate-limiting step. This work provides a clear view of the debut on the rate-limiting step of the alkane oxidation. It should be a significant step forward for understanding the relationship between the porphyrin molecular structures and catalytic activity accurately and for predicting and designing high-activity catalysts.     

Reduction potentials of seventy-five free base porphyrin molecules: Reactivity correlations and the prediction of potentials

Phase sensitive fundamental harmonic ac voltammetric techniques have been used to measure the reduction potentials of seventy-five metal-free meso and β-pyrrole substituted porphyrins in DMF solution. Correlations are explored between the reduction potentials and porphyrin and metalloporphyrin reactivity. Such porphyrin reduction potentials can be reliably predicted using assigned substitutent partial potential values.     

How axial ligands control the reactivity of high-valent iron(IV)-oxo porphyrin pi-cation radicals in alkane hydroxylation: a computational study

The push effect of anionic axial ligands of high-valent iron(IV)-oxo porphyrin pi-cation radicals, (Porp)(+.)Fe(IV)(O)(X) (X=OH(-), AcO(-), Cl(-), and CF(3)SO(3)(-)), in alkane hydroxylation is investigated by B3LYP DFT calculations. The electron-donating ability of anionic axial ligands influences the activation energy for the alkane hydroxylation by the iron(IV)-oxo intermediates and the Fe-O bond distance of the iron-oxo species in transition state.     

Improvement of porphyrin cellular delivery and activity by conjugation to a carrier peptide

The chemical nuclease metalloporphyrin (manganese(III) porphyrin) can cleave DNA irreversibly and can thus constitute a potential antitumor drug. However, these molecules show low permeability to cell surface membranes. We report here the conjugation of an amphipathic carrier peptide to improve considerably its cellular delivery. The metalloporphyrin-peptide conjugate can be internalized by cells within only 5 min of incubation with a yield as high as 80%. Furthermore, the metalloporphyrin-peptide conjugate is able to cleave in vitro high or low molecular weight DNA to the same extend as metalloporphyrin alone without affecting the sequence-specific cleaving activity of the porphyrin. The conjugate is 100-fold more efficient at inducing tumor cells death than the free metalloporphyrin via a mechanism involving genomic DNA cleavage. The results are promising for further therapeutic applications with antitumor drugs such as metalloporphyrin, and also with other existing drugs by using a carrier peptide system in order to improve the cellular uptake of such molecules.     

High-valent nonheme iron-oxo species in biomimetic oxidations

High valent iron-oxo species are often invoked as the key oxidizing agents in the catalytic cycles of oxygen activating nonheme iron enzymes, and three of these intermediates have in fact been characterized. To gain further insight into such species, a number of biomimetic complexes have been designed and investigated as functional models for these enzymes. Progress since 2000 is summarized in this review. Many of the model complexes discussed in this review carry out oxidative transformations of relevance to the enzymatic reactions; however, the participation of a high-valent iron-oxo species (Fe(IV)O or Fe(V)O) can only be inferred. Arguments in support of a metal-based oxidant (rather than an oxygen radical species) usually hinge on the high conversion for the transformation and the nature of the reaction products, as well as the incorporation of label into these products from H(2)(18)O or related species. Within this time period, the first bona fide nonheme Fe(IV)O complexes have been generated and identified spectroscopically, three of which are crystallographically characterized. Taken together, these studies emphasize the important role the supporting polydentate ligand plays in eliciting the desired high-valent iron-oxo chemistry.     

Enzymatic C-H activation by metal-superoxo intermediates

The mechanisms of four enzymes that initiate oxidation of their substrates by using mid-valent metal-superoxo intermediates, rather than the more frequently described high-valent iron-oxo complexes, to cleave relatively strong C-H bonds have come into focus in the past several years. In two of these reactions, the alternative manifold for O2 and C-H activation enables unique four-electron oxidation reactions, thus significantly augmenting Nature's arsenal for transformation of aliphatic carbon compounds. General principles of this alternative manifold, including common kinetic characteristics and thermodynamic limitations, are emerging. Recent, combined experimental and computational studies on other systems have shown how a more thorough understanding of the structures of the metal-superoxo intermediates and the mechanisms by which they cleave C-H bonds might be achieved.     

17O NMR study of oxo metalloporphyrin complexes: correlation with electronic structure of M=O moiety

(17)O NMR spectroscopy of oxo ligand of oxo metalloporphyrin can be considered as an excellent means to derive information about structure, electronic state, and reactivity of the metal bound oxo ligand. To show the utility of (17)O NMR spectroscopy of oxo ligand of oxo metalloporphyrin, (17)O NMR spectra of oxo ligands of dioxo ruthenium(VI), oxo chromium(IV), and oxo titanium(IV) porphyrins are measured. For all oxo metalloporphyrins, well-resolved (17)O NMR signals are detected in far high frequency region. The (17)O NMR signal of the metal bound oxo ligand shifts high frequency in order of Ru(VI)相似文献   

Extracellular heme peroxidases in actinomycetes: a case of mistaken identity

Actinomycetes secrete into their surroundings a suite of enzymes involved in the biodegradation of plant lignocellulose; these have been reported to include both hydrolytic and oxidative enzymes, including peroxidases. Reports of secreted peroxidases have been based upon observations of peroxidase-like activity associated with fractions that exhibit optical spectra reminiscent of heme peroxidases, such as the lignin peroxidases of wood-rotting fungi. Here we show that the appearance of the secreted pseudoperoxidase of the thermophilic actinomycete Thermomonospora fusca BD25 is also associated with the appearance of a heme-like spectrum. The species responsible for this spectrum is a metalloporphyrin; however, we show that this metalloporphyrin is not heme but zinc coproporphyrin. The same porphyrin was found in the growth medium of the actinomycete Streptomyces viridosporus T7A. We therefore propose that earlier reports of heme peroxidases secreted by actinomycetes were due to the incorrect assignment of optical spectra to heme groups rather than to non-iron-containing porphyrins and that lignin-degrading heme peroxidases are not secreted by actinomycetes. The porphyrin, an excretory product, is degraded during peroxidase assays. The low levels of secreted peroxidase activity are associated with a nonheme protein fraction previously shown to contain copper. We suggest that the role of the secreted copper-containing protein may be to bind and detoxify metals that can cause inhibition of heme biosynthesis and thus stimulate porphyrin excretion.     

Valence-tautomerism in high-valent iron and manganese porphyrins

Iron and manganese hemes are "high-valent" when the valence state of the metal exceeds III. Redox chemistry of the high valent metal complexes involves redistribution of holes and electrons over the metal ion and the porphyrin and axial ligands, defined as valence tautomerism. Thus, catalytic pathways of heme-containing biomolecules such as peroxidases, catalases and cytochromes P450 involve valence tautomerism, as do pathways of biomimetic oxygen transfer catalysis by manganese porphyrins, robust catalysts with potential commercial value. Determinants of the site of electron abstraction are key to understanding valence tautomerism. In model systems, metal-centered oxidation is supported by hard anionic axial ligands that are also strongly pi-donating, such as oxo, aryl, bix-methoxy and bis-fluoro groups. Manganese(IV) is more stable than iron(IV) and metal-centered one-electron oxidations occur with weaker pi-donating axial ligands such as bisazido, -isocyanato, -hypochlorito and bis chloro groups. Virtually all known high-valent iron porphyrin complexes oxidized by two-electrons above the ferric state are coordinated by the strongly pi-donating oxo or nitrido ligands. In all well-characterized oxo complexes, iron is in the ferryl state and the second oxidizing equivalent resides on the porphyrin. Complexes with iron(V) have not been definitively characterized. One-electron oxidation of oxomanganese(IV) porphyrin complexes gives the oxomanganese(IV) porphyrin pi-cation redicals. In aqueous solution, oxidation of Mn(III) complexes of tetra cationic N-methylpyridiniumylporphyrin isomers by monooxygen donors yields a transient oxomanganese(V) species.     

Spectroscopy and electronic structures of mono- and binuclear high-valent non-heme iron-oxo systems

High-valent iron-oxo intermediates are known or believed to be key oxidizing species in the catalytic mechanisms of many mononuclear and binuclear non-heme iron enzymes. So far only limited experimental data on their electronic structures are available. In this study we extend knowledge from the experimentally well characterized mononuclear Fe(IV)=O (S=1) biomimetic model system to computational insight into the spectroscopy and electronic structures of mono-and binuclear high-valent iron-oxo enzyme intermediates. In the mononuclear Fe(IV)=O complexes, we predict the spectroscopy and energies of the electronic transitions to be very different for the S=1 and S=2 spin states, but the iron-oxo bonding for both spin states to be very similar. A comparison of the S=2 mono- and binuclear high-valent iron-sites predicts similar electronic transitions. However, the bent iron-oxo bridge and interactions with the second iron-center in the dimer shift the transitions to higher energies and splits the d(xz/yz) orbital set. These electronic structure and TD-DFT results provide a basis for understanding the spectroscopy and electronic structures of high-valent intermediates in mono- and binuclear non-heme iron enzymes.     

Effect of dietary tetrapyrroles on gut pigmentation and perienteric fluid hemoglobin concentration in Ascaris lumbricoides

Ascaris lumbricoides was maintained for 46 days in three pigs fed diets enriched with different metalloporphyrins. Diets, host gut contents, and washed worm guts were differentially extracted for carotenoids, bile pigments, porphyrins and metalloporphyrins, and extracts were compared by spectrophotometric and qualitative chemical tests. Host gut contents from a control diet with no added porphyrin contained carotenoids and bilirubin; worms from this host contained bilirubin and an unidentified metalloporphyrin. An alfalfa-enriched diet yielded phaeophytin A in host gut contents, while worm gut tissue contained an unidentified metalloporphyrin different from the controls. Host gut contents and worms from a blood meal-enriched diet both contained protoheme IX; perienteric fluid concentration in these worms (0·211 mM) was five times that of the other groups. The presence of metalloporphyrins in guts of worms reared on linear tetrapyrroles suggests the ability to convert these compounds to heme.     

The reaction mechanisms of heme catalases: an atomistic view by ab initio molecular dynamics

Catalases are ubiquitous enzymes that prevent cell oxidative damage by degrading hydrogen peroxide to water and oxygen (2H(2)O(2) → 2H(2)O+O(2)) with high efficiency. The enzyme is first oxidized to a high-valent iron intermediate, known as Compound I (Cpd I, Por(·+)-Fe(IV)=O) which, at difference from other hydroperoxidases, is reduced back to the resting state by further reacting with H(2)O(2). The normal catalase activity is reduced if Cpd I is consumed in a competing side reaction, forming a species named Cpd I*. In recent years, Density Functional Theory (DFT) methods have unraveled the electronic configuration of these high-valent iron species, helping to assign the intermediates trapped in the crystal structures of oxidized catalases. It has been demonstrated that the a priori assumption that the H(+)/H(-) type of mechanism for Cpd I reduction leads to the generation of singlet oxygen is not justified. Moreover, it has been shown by ab initio metadynamics simulations that two pathways are operative for Cpd I reduction: a His-mediated mechanism (described as H·/H(+) + e(-)) in which the distal His acts as an acid-base catalyst and a direct mechanism (described as H·/H·) in which the distal His does not play a direct role. Independently of the mechanism, the reaction proceeds by two one-electron transfers rather than one two-electron transfer, as previously assumed. Electron transfer to Cpd I, regardless of whether the electron is exogenous or endogenous, facilitates protonation of the oxoferryl group, to the point that formation of Cpd I* may be controlled by the easiness of protonation of reduced Cpd I.     

Extracellular Heme Peroxidases in Actinomycetes: a Case of Mistaken Identity

Actinomycetes secrete into their surroundings a suite of enzymes involved in the biodegradation of plant lignocellulose; these have been reported to include both hydrolytic and oxidative enzymes, including peroxidases. Reports of secreted peroxidases have been based upon observations of peroxidase-like activity associated with fractions that exhibit optical spectra reminiscent of heme peroxidases, such as the lignin peroxidases of wood-rotting fungi. Here we show that the appearance of the secreted pseudoperoxidase of the thermophilic actinomycete Thermomonospora fusca BD25 is also associated with the appearance of a heme-like spectrum. The species responsible for this spectrum is a metalloporphyrin; however, we show that this metalloporphyrin is not heme but zinc coproporphyrin. The same porphyrin was found in the growth medium of the actinomycete Streptomyces viridosporus T7A. We therefore propose that earlier reports of heme peroxidases secreted by actinomycetes were due to the incorrect assignment of optical spectra to heme groups rather than to non-iron-containing porphyrins and that lignin-degrading heme peroxidases are not secreted by actinomycetes. The porphyrin, an excretory product, is degraded during peroxidase assays. The low levels of secreted peroxidase activity are associated with a nonheme protein fraction previously shown to contain copper. We suggest that the role of the secreted copper-containing protein may be to bind and detoxify metals that can cause inhibition of heme biosynthesis and thus stimulate porphyrin excretion.     

Molecular orbital study of porphyrin-substrate interactions in cytochrome P450 catalysed aromatic hydroxylation of substituted anilines

The reaction mechanism for the primary reaction step of the hydroxylation of 3-fluoro-6-methylaniline, attacked at different positions (oxygen attack across a C-C bond and direct attack at positions para and ortho with respect to the NH(2)-group) catalysed by a high-valent ferryl-oxo porphyrin a(2u)-cation complex with H(3)CS(-) as an axial ligand, has been investigated on the basis of electronic structure calculations in local spin-density approximation. Non-repulsive potential curves are obtained only in cases of direct attack at the para- and ortho-positions with respect to NH(2), but not for epoxide formation. Comparing the potential curves for the hydroxylation at the positions para and ortho to the NH(2)-group, an attack at the para-position is more likely. The relative orientation of the substrate towards the porphyrin is essentially determined by the interaction between the substituents of the substrate and the porphyrin. Consequently, different geometrical orientations of the substrate are obtained for hydroxylation at the para- and ortho-positions. In both cases of direct attack the substrate plane is not parallel to the porphyrin plane. The decisive role of sulphur in the hydroxylation is demonstrated by the participation of the S(3p)-orbitals in all molecular orbitals involved in the reaction.     

In vitro toxicity of palladium(II) and gold(III) porphyrins and their aqueous metal ion counterparts on Trypanosoma brucei brucei growth

The trypanocidal effects of aqueous gold(III) and palladium(II) and their metalloporphyrin derivatives on Trypanosoma brucei brucei growth in culture have been studied using an Alamar Blue indicator assay. All the experiments were conducted in the dark. As previously described for mercury(II), cadmium(II) and lead(II) porphyrins [Chem.-Biol. Interact. 139 (2002) 177], the toxicity of the metalloporphyrin complex of palladium(II) to T. b. brucei parasites was much higher compared to the aqueous free palladium(II) and free base porphyrin. Palladium(II) porphyrin, free palladium(II), and the free base porphyrin were trypanocidal to T. b. brucei at concentrations >1.5 x 10(-6), >6.1 x 10(-6) and >1.9 x 10(-5) M, respectively. While gold(III) porphyrin was effective against the parasites at concentrations >4.8 x 10(-6) M, its aqueous gold(III) was toxic at concentrations as low as 2.0 x 10(-7) M due to the generation of free radicals in the presence of this metal ion which enhanced its toxicity to the T. b. brucei parasites. Although some cell division was observed in some of the cells treated with palladium(II) porphyrin, some dividing cells had no nucleus due to unequal division and delivery of the nuclei into the daughter cells. As a result, the rate of cell division decreased with time and cell death occurred within 24 h. Interestingly, trypanosomes treated with metalloporphyrin complexes displayed different morphological features from those cells treated with free base porphyrin or metal ions. Of all the porphyrins and free metal ions tested, only mercury(II) porphyrin and aqueous gold(III) ion were toxic to the trypanosomes in the 10(-7) M range. The chemotherapeutic potential of these observations is discussed.     

High-valent iron in chemical and biological oxidations

Various aspects of the reactivity of iron(IV) in chemical and biological systems are reviewed. Accumulated evidence shows that the ferryl species [Fe(IV)O](2+) can be formed under a variety of conditions including those related to the ferrous ion-hydrogen peroxide system known as Fenton's reagent. Early evidence that such a species could hydroxylate typical aliphatic C-H bonds included regioselectivities and stereospecificities for cyclohexanol hydroxylation that could not be accounted for by a freely diffusing hydroxyl radical. Iron(IV) porphyrin complexes are also found in the catalytic cycles of cytochrome P450 and chloroperoxidase. Model oxo-iron(IV) porphyrin complexes have shown reactivity similar to the proposed enzymatic intermediates. Mechanistic studies using mechanistically diagnostic substrates have implicated a radical rebound scenario for aliphatic hydroxylation by cytochrome P450. Likewise, several non-heme diiron hydroxylases, AlkB (Omega-hydroxylase), sMMO (soluble methane monooxygenase), XylM (xylene monooxygenase) and T4moH (toluene monooxygenase) all show clear indications of radical rearranged products indicating that the oxygen rebound pathway is a ubiquitous mechanism for hydrocarbon oxygenation by both heme and non-heme iron enzymes.     

Structures of the high-valent metal-ion haem-oxygen intermediates in peroxidases, oxygenases and catalases

Peroxidases, oxygenases and catalases have similar high-valent metal-ion intermediates in their respective reaction cycles. In this review, haem-based examples will be discussed. The intermediates of the haem-containing enzymes have been extensively studied for many years by different spectroscopic methods like UV-Vis, EPR (electron paramagnetic resonance), resonance Raman, M?ssbauer and MCD (magnetic circular dichroism). The first crystal structure of one of these high-valent intermediates was on cytochrome c peroxidase in 1987. Since then, structures have appeared for catalases in 1996, 2002, 2003, putatively for cytochrome P450 in 2000, for myoglobin in 2002, for horseradish peroxidase in 2002 and for cytochrome c peroxidase again in 1994 and 2003. This review will focus on the most recent structural investigations for the different intermediates of these proteins. The structures of these intermediates will also be viewed in light of quantum mechanical (QM) calculations on haem models. In particular quantum refinement, which is a combination of QM calculations and crystallography, will be discussed. Only small structural changes accompany the generation of these intermediates. The crystal structures show that the compound I state, with a so called pi-cation radical on the haem group, has a relatively short iron-oxygen bond (1.67-1.76A) in agreement with a double-bond character, while the compound II state or the compound I state with a radical on an amino acid residue have a relatively long iron-oxygen bond (1.86-1.92A) in agreement with a single-bond character where the oxygen-atom is protonated.