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A series of metallophthalocyanine (PcM) complexes with axial N-heterocyclic carbene ligands (NHC; 1,3-diisopropylimidazol-2-ylidene (DIP) and 1,3-dimethylbenzimidazol-2-ylidene (DMB)) were prepared and structurally characterized. PcCoII(DIP), PcZnII(DIP), and PcZnII(DMB) are five-coordinate complexes with mild dome-type Pc-ring distortions, while PcFeII(DIP)2 is six-coordinate and has a very large ruffle-type ring-distortion with respect to typical PcM(L)2 systems. The distortion is induced by the highly steric axial DIP ligands. The distortions were quantified and classified by their bond lengths and torsion angles, and according to the normal-coordinate structural decomposition (NSD) analysis. Upon ligation of the NHC, the insoluble PcM materials were solublized in common organic solvents, with typical UV-visible Q-band maxima observable between 658 and 677 nm; the increased solubility is rationalized in terms of the reduced solid-state aggregation of the complexes, attributable to the axial ligation. [ABSTRACT FROM AUTHOR]

Redox reactions of the aromatic amino acids tyrosine (Tyr) and tryptophan (Trp) are crucial for the biological functions of many metalloproteins. An important question is how biological systems can use the protein environment to move electrons through proteins in a controlled manner. Methionine (Met)-aromatic interactions are common in proteins, but little is known about redox reactions of such motifs. Here, we explore methionine sulfur-aromatic interactions in the oxidoreductase (EC 1) class of proteins and their proximity to metal sites. We also propose a new metric for classifying Met-aromatic interactions called “interaction order.” Over 12,000 protein structures from the Protein Data Bank were analyzed. A linear algebraic heuristic was used to classify the interaction of Met‑sulfur with tyrosine, tryptophan, and phenylalanine. We found that 83% of oxidoreductase proteins contained aromatic interactions meeting our criteria, with a preferential angle of about 60° between Met‑sulfur lone pairs and aromatic planes. A total of 41% of Met-aromatic interactions meeting our criteria were found to be within 20 Å of a metal site, and 6% were found within 10 Å. A surprising number of “bridging” interactions, involving two aromatic residues and one Met also were identified. Finally, selected examples of potentially important Met-aromatic redox motifs are outlined. On the basis of our results, we suggest that Met-aromatic interactions should be considered as mediators of electron transfer reactions, as well as their more widely recognized roles as structural motifs. [ABSTRACT FROM AUTHOR]

A series of ClRe(CO)3-containing complexes with 1-methyl-1 H-benzo[ d]imidazol-2-yl)quinoline (Me-QuBIm), 1-benzyl-1 H-benzo[ d]imidazol-2-yl)quinoline (Bn-QuBIm), and 2-(1-(4-methoxybenzyl)-1 H-benzo[ d]imidazol-2-yl)quinoline (OMeBn-QuBIm) ligands were prepared and characterized. Each complex was characterized using 1H and 13C NMR, infrared, UV-vis, and fluorescence spectroscopies, and cyclic voltammetry. The physical properties of each complex are similar to the parent ClRe(CO)3(2-(1 H-benzo[ d]imidazol-2-yl)quinoline) complex. However, the electrochemical behavior is distinct from the parent, showing reversible voltammograms and poor CO2 reduction activity. Addition of K+ or Mg2+ as Lewis acids modestly increases catalytic currents, but at large overpotentials. The work presented here is consistent with a mechanism that involves rhenium reduction and deprotonation of imidazole and benzimidazole prior to CO2 reduction electrocatalysis. [ABSTRACT FROM AUTHOR]

Metallophthalocyanine (PcM) coordination complexes are well-known mediators of the electrochemical reduction of carbon dioxide (CO2). They have many properties that show promise for practical applications in the energy sector. Such properties include synthetic flexibility, a high stability, and good efficiencies for the reduction of CO2 to useful feedstocks, such as carbon monoxide (CO). One of the ongoing challenges that needs to be met is the incorporation of PcM into the heterogeneous materials that are used in a great many CO2-reduction devices. Much progress has been made in the last decade and there are now several promising approaches to incorporate PcM into a range of materials, from simple carbon-adsorbed preparations to extended polymer networks. These approaches all have important advantages and drawbacks. In addition, investigations have led to new proposals regarding CO2 reduction catalytic cycles and other operational features that are crucial to function. Here, we describe developments in the immobilization of PcM CO2 reduction catalysts in the last decade (2013 to 2023) and propose promising avenues and strategies for future research. [ABSTRACT FROM AUTHOR]

An enormous variety of biological redox reactions are accompanied by changes in proton content at enzyme active sites, in their associated cofactors, in substrates and/or products, and between protein interfaces. Understanding this breadth of reactivity is an ongoing chemical challenge. A great many workers have developed and investigated biomimetic model complexes to build new ways of thinking about the mechanistic underpinnings of such complex biological proton-coupled electron transfer (PCET) reactions. Of particular importance are those model reactions that involve transfer of one proton (H+) and one electron (e- ), which is equivalent to transfer of a hydrogen atom (H•). In this Current Topic, we review key concepts in PCET reactivity and describe important advances in biomimetic PCET chemistry, with a special emphasis on research that has enhanced efforts to understand biological PCET reactions. [ABSTRACT FROM AUTHOR]

The geometrical model introduced previously by the authors has been extended quantitatively to document changes in angular correlations between and among residues as azurin unfolds. In the early stages of denaturation, these changes are found to be more pronounced than changes in the spatial displacement of residues, a result that is also found for residues acting in concert, viz., α-helices, β-sheet residues and residues in ‘turning regions.’ Our analysis leads to a picture of the large-scale motion of the polypeptide chain as azurin denatures. Flanking a central ‘ribbon’ of residues whose orientation remains essentially invariant, we find that in the early stages of unfolding, left- and right-hand ‘wings’ adjacent to this stationary scaffolding pivot counterclockwise, while smaller regions on opposing ends of the β-barrel pivot clockwise. As spatial constraints characterising the native state are further relaxed, our calculations show that some regions reverse their orientational motion, reflecting the enhanced flexibility of the polypeptide chain in the denatured state. [ABSTRACT FROM AUTHOR]

We have designed ruthenium-modified Pseudomonas aeruginosa azurins that incorporate 3-nitrotyrosine (NO2YOH) between Ru(2,2′-bipyridine)2(imidazole)(histidine) and Cu redox centers in electron transfer (ET) pathways. We investigated the structures and reactivities of three different systems: RuH107NO2YOH109, RuH124NO2YOH122, and RuH126NO2YOH122. RuH107NO2YOH109, unlabeled H124NO2YOH122, and unlabeled H126NO2YOH122 were structurally characterized. The pKa's of NO2YOH at positions 122 and 109 are 7.2 and 6.0, respectively. Reduction potentials of 3-nitrotyrosinate (NO2YO-)-modified azurins were estimated from cyclic and differential pulse voltammetry data: oxidation of NO2YO-122 occurs near 1.1 versus NHE; oxidation of NO2YO-109 is near 1.2 V. Our analysis of transient optical spectroscopic experiments indicates that hopping via NO2YO- enhances CuI oxidation rates over single-step ET by factors of 32 (RuH107NO2YO-109), 46 (RuH126NO2YO-122), and 13 (RuH124NO2YO-122). [ABSTRACT FROM AUTHOR]

Abstract: We report the kinetics of CO rebinding to the heme in His134Ser, Ile223Val and His134Ser/Ile223Ser mutants of Geobacillus stearothermophilus nitric oxide synthase (gsNOS). The amplitudes of the two observed kinetics phases, which are insensitive to CO concentration, depend on enzyme concentration. We suggest that two forms of gsNOS are in equilibrium under the conditions employed (6.1–27μM gsNOS with 20 or 100% CO atmosphere). The kinetics of CO rebinding to the heme do not depend on the identity of the NO-gate residues at positions 134 and 223. [Copyright &y& Elsevier]

We investigate the stability to structural perturbation ofPseudomonas aeruginosaazurin using a previously developed geometric model. Our analysis considers Ru(2,2′,6′,2″-terpyridine)(1,10-phenanthroline)(His83)-labelled wild-type azurin and five variants with mutations to Cu-ligating residues. We find that in the early stages of unfolding, the β-strands exhibit the most structural stability. The conserved residues comprising the hydrophobic core are dislocated only after nearly complete unfolding of the β-barrel. Attachment of the Ru-complex at His83 does not destabilize the protein fold, despite causing some degree of structural rearrangement. Replacing the Cys112 and/or Met121 Cu ligands does not affect the conformational integrity of the protein. Notably, these results are in accord with experimental evidence, as well as molecular dynamics simulations of the denaturation of azurin. [ABSTRACT FROM PUBLISHER]

Abstract: Photosynthetic reaction centers (PRCs) employ multiple-step tunneling (hopping) to separate electrons and holes that ultimately drive the chemistry required for metabolism. We recently developed hopping maps that can be used to interpret the rates and energetics of electron/hole hopping in three-site (donor–intermediate–acceptor) tunneling reactions, including those in PRCs. Here we analyze several key ET reactions in PRCs, including forward ET in the L-branch, and hopping that could involve thermodynamically uphill intermediates in the M-branch, which is ET-inactive in vivo. We also explore charge recombination reactions, which could involve hopping. Our hopping maps support the view that electron flow in PRCs involves strong electronic coupling between cofactors and reorganization energies that are among the lowest in biology (≤0.4eV). [Copyright &y& Elsevier]

Abstract: Biological redox machines require efficient transfer of electrons and holes for function. Reactions involving multiple tunneling steps, termed “hopping,” often promote charge separation within and between proteins that is essential for energy storage and conversion. Here we show how semiclassical electron transfer theory can be extended to include hopping reactions: graphical representations (called hopping maps) of the dependence of calculated two-step reaction rate constants on driving force are employed to account for flow in a rhenium-labeled azurin mutant as well as in two structurally characterized redox enzymes, DNA photolyase and MauG. Analysis of the 35Å radical propagation in ribonucleotide reductases using hopping maps shows that all tyrosines and tryptophans on the radical pathway likely are involved in function. We suggest that hopping maps can facilitate the design and construction of artificial photosynthetic systems for the production of fuels and other chemicals. [Copyright &y& Elsevier]

Abstract: Blue copper proteins (BCPs) comprise classic cases of Nature''s profound control over the electronic structures and chemical reactivity of transition metal ions. Early studies of BCPs focused on their inner coordination spheres, that is, residues that directly coordinate Cu. Equally important are the electronic and geometric perturbations to these ligands provided by the outer coordination sphere. In this tribute to Hans Freeman, we review investigations that have advanced the understanding of how inner-sphere and outer-sphere coordination affects biological Cu properties. [Copyright &y& Elsevier]

Abstract: Redox reactions of tyrosine play key roles in many biological processes, including water oxidation and DNA synthesis. We first review the redox properties of tyrosine (and other phenols) in small molecules and related polypeptides, then report work on (H20)/(Y48)-modified Pseudomonas aeruginosa azurin. The crystal structure of this protein (1.18Å resolution) shows that H20 is strongly hydrogen bonded to Y48 (2.7–2.8Å tyrosine-O to histidine-N distance). A firm conclusion is that proper tuning of the tyrosine potential by a proton-accepting base is critical for biological redox functions. [Copyright &y& Elsevier]

We have investigated the kinetics of NO escape from Geobacillus stearothermophilus nitric oxide synthase (gsNOS). Previous work indicated that NO release was gated at position 223 in mammalian enzymes; our kinetics experiments include mutants at that position along with measurements on the wild type enzyme. Employing stopped-flow UV-vis methods, reactions were triggered by mixing a reduced enzyme/N-hydroxy-l-arginine complex with an aerated buffer solution. NO release kinetics were obtained for wt NOS and three mutants (H134S, I223V, H134S/I223V). We have confirmed that wt gsNOS has the lowest NO release rate of known NOS enzymes, whether bacterial or mammalian. We also have found that steric clashes at positions 223 and 134 hinder NO escape, as judged by enhanced rates in the single mutants. The empirical rate of NO release from the gsNOS double mutant (H134/I223V) is nearly as rapid as that of the fastest mammalian enzymes, demonstrating that both positions 223 and 134 function as gates for escape of the product diatomic molecule. [ABSTRACT FROM AUTHOR]

A heme model system has been developed in which the heme-propionate is the only proton donating/accepting site, using protoporphyrin IX-monomethyl esters (PPDIXMME) and N-methylimidazole (MeIm). Proton-coupled electron transfer (PCET) reactions of these model compounds have been examined in acetonitrile solvent. (PPDMME)FeII(MeIm)2-propionate (FeIII∼CO2) is readily reduced by the ascorbate derivative 5,6-isopropylidine ascorbate to give (PPIXMME)FeII(MeIm)2-propionic add (FeII∼CO2H). An excess of the hydroxylamine TEMPOH or of hydroquinone similarly reduces FeIII∼CO2, and TEMPO and benzoquinone oxidize FeII∼CO2H to return to FeIII∼CO2, The measured equilibrium constants and the determined pKa and E1/2 values, indicate that FeII∼CO2H has an effective bond dissociation free energy (BDFE) of 67.8 ± 0.6 kcal mol-1. In these PPIX models, electron transfer occurs at the iron center and proton transfer occurs at the remote heme propionate. According to thermochemical and other arguments, the TEMPOH reaction occurs by concerted proton-electron transfer (CPET), and a similar pathway is indicated for the ascorbate derivative. Based on these results, heme propionates should be considered as potential key components of PCET/ CPET active sites in heme proteins. [ABSTRACT FROM AUTHOR]

The article analyzes the thermochemical properties of reagents that transfer electrons and protons. Particular focus is given on the mechanisms of specific H+/e- transfer reactions and their link with hydrogen atom transfers (HAT) and X-H homolytic bond strengths. A discussion on HAT is detailed. Other topics discussed include a comparison between concerted proton-electron transfer (CPET) and stepwise pathways, and thermochemistry of PCET reagents like hydroxylamines, phenols and ascorbate, among others.

Ascorbate (vitamin C) is a ubiquitous biological cofactor. While its aqueous solution chemistry has long been studied, many in vivo reactions of ascorbate occur in enzyme active sites or at membrane interfaces, which have varying local environments. This report shows that the rate and driving force of oxidations of two ascorbate derivatives by the TEMPO radical (2,2̲,6,6̲-tetramethylpiperidin-1-oxyl) in acetonitrile are very sensitive to the presence of various additives. These reactions proceed by the transfer of a proton and an electron (a hydrogen atom), as is typical of biological ascorbate reactions. The measured rate and equilibrium constants vary substantially with added water or other polar solutes in acetonitrile solutions, indicating large shifts in the reducing power of ascorbate. The correlation of rate and equilibrium constants indicates that this effect has a thermochemical origin rather than being a purely kinetic effect. This contrasts with previous examples of solvent effects on hydrogen atom transfer reactions. Potential biological implications of this apparently unique effect are discussed. [ABSTRACT FROM AUTHOR]

Chemical reactions that involve net hydrogen atom transfer (HAT) are ubiquitous in chemistry and biology, from the action of antioxidants to industrial and metalloenzyme catalysis. This report develops and validates a procedure to predict rate constants for HAT reactions of oxyl radicals (RO') in various media. Our procedure uses the Marcus cross relation (CR) and includes adjustments for solvent hydrogen-bonding effects on both the kinetics and thermodynamics of the reactions. Kinetic solvent effects (KSE5) are included by using lngold's model, and thermodynamic solvent effects are accounted for by using an empirical model developed by Abraham. These adjustments are shown to be critical to the success of ourcombined model, referred to as the CR/KSE model. As an initial test of the CR/KSE model we measured self-exchange and cross rate constants in different solvents for reactions of the 2,4,6-tri-tert-butylphenoxyl radical and the hydroxylamine 2,2'-6,6'-tetramethylpiperidin-1-ol. Excellent agreement is observed between the calculated and directly determined cross rate constants. We then extend the model to over 30 known HAT reactions of oxyl radicals with OH or CH bonds, including biologically relevant reactions of ascorbate, peroxyl radicals, and a-tocopherol. The CR/KSE model shows remarkable predictive power, predicting rate constants to within a factor of 5 for almost all of the surveyed HAT reactions. [ABSTRACT FROM AUTHOR]

Abstract: The prospects for using bacterial DNA as an intrinsic probe for HOCl and secondary oxidants/chlorinating agents associated with it has been evaluated using both in vitro and in vivo studies. Single-strand and double-strand breaks occurred in bare plasmid DNA that had been exposed to high levels of HOCl, although these reactions were very inefficient compared to polynucleotide chain cleavage caused by the OH -generating reagent, peroxynitrite. Plasmid nicking was not increased when intact Escherichia coli were exposed to HOCl; rather, the amount of recoverable plasmid diminished in a dose-dependent manner. At concentration levels of HOCl exceeding lethal doses, genomic bacterial DNA underwent extensive fragmentation and the amount of precipitable DNA–protein complexes increased several-fold. The 5-chlorocytosine content of plasmid and genomic DNA isolated from HOCl-exposed E. coli was also slightly elevated above controls, as measured by mass spectrometry of the deaminated product, 5-chlorouracil. However, the yields were not dose-dependent over the bactericidal concentration range. Genomic DNA recovered from E. coli that had been subjected to phagocytosis by human neutrophils occasionally showed small increases in 5-chlorocytosine content when compared to analogous cellular reactions where myeloperoxidase activity was inhibited by azide ion. Overall, the amount of isolable 5-chlorouracil from the HOCl-exposed bacterial cells was far less than the damage manifested in polynucleotide bond cleavage and cross-linking. [Copyright &y& Elsevier]

The author cites two studies that demonstrate how reduction potentials in proteins can be rationally tuned using primarily outer-sphere mutations. Topics discussed include the use of azurin as a framework that can be rationally modify to shift reduction potentials of the embedded metal site, the results of a study that tuned reduction potentials in azurin with mutations to onley three residues, and the design of modified proteins relevant to energy and the environment.

The article discusses the reaction of porphyrin-iron-bis(imidazole) complexes by hydrogen atom transfer (HAT). According to the authors, the porphyrin-imidazole complexes have been developed as structural, spectroscopic and electron-transfer models for the growing family of bis(histidine)-ligated heme proteins. They add that HAT reactions should be considered as part of the primary arsenal of reactivity of histidine-ligated heme cofactors.

The amino acid residue methionine (Met) is commonly thought of as a ligand in redox metalloproteins, for example in cytochromes c and in blue copper proteins. However, the roles of Met can go beyond a simple ligand. The thioether functional group of Met allows it to be considered as a hydrophobic residue as well as one that is capable of weak dipolar interactions. In addition, the lone pairs on sulphur allow Met to interact with other groups, inluding the aforementioned metal ions. Because of its properties, Met can play diverse roles in metal coordination, fine tuning of redox reactions, or supporting protein structures. These roles are strongly influenced by the nature of the surrounding medium. Herein, we describe several common interactions between Met and surrounding aromatic amino acids and how they affect the physical properties of both copper and iron metalloproteins. While the importance of interactions between Met and other groups is established in biological systems, less is known about their roles in redox metalloproteins and our view is that this is an area that is ready for greater attention. [ABSTRACT FROM AUTHOR]

Multi-step electron transfer reactions are important to the function of many cellular systems. The ways in which such systems have evolved to direct electrons along specific pathways are largely understood, but less so are the ways in which the reduction–oxidation potentials of individual redox sites are controlled. We prepared a series of three new artificial variants of Pseudomonas aeruginosa azurin where a tyrosine (Tyr109) is situated between the native Cu ion and a Ru(II) photosensitizer tethered to a histidine (His107). Arginine, glutamine, or methionine were introduced as position 122, which is near to Tyr109. We investigated the rate of CuI oxidation by a flash-quench generated Ru(III) oxidant over pH values from 5 to 9. While the identity of the residue at position 122 affects some of the physical properties of Tyr109, the rates of CuI oxidation are only weakly dependent on the identity of the residue at 122. The results highlight that more work is still needed to understand how non-covalent interactions of redox active groups are affected in redox proteins. [ABSTRACT FROM AUTHOR]

Many types of non-covalent interactions give rise to a protein's natural structure and function. One such interaction involves an aromatic amino acid (phenylalanine (Phe), tryptophan (Trp), or tyrosine (Tyr)) and the sulfur of methionine (Met), the so-called methionine-aromatic interaction. The Met-aromatic interaction is well-established, and it is defined as involving one aromatic and one Met residue. However, in a small-scale survey, we recently noted that more than one aromatic residue can interact with one Met in a "bridging" motif of the general form Aro-Met-Aro. In the present work, a systematic survey of all protein structures available in the Protein Data Bank was carried out. About 70% of those structures contain any Met-aromatic interaction and over 40% contain a Met-aromatic bridge. Analysis of a smaller subset of protein structures, which omits entries with low resolution or high sequence homology, shows the same distribution. The relationship of bridging interactions and longer aromatic amino acid chains also was explored using network theory approaches. Met-Aro bridges were found in 8.4% of extended aromatic chains. Analysis of a different subset of proteins that contain embedded metal ions as reference points revealed that many Met-Aro bridges are at/near protein surfaces. These analyses, and some specific examples, lead to the proposal that Met-aromatic bridges play biological roles as stabilizers and protectors of protein structures, motifs for molecular recognition, and electron transfer mediators. Image 1 • Interactions of one methionine and two aromatic residues are discussed. • These interactions are found in 40% of structurally characterized proteins. • Proposed roles include molecular recognition, protein folding, and electron transfer. [ABSTRACT FROM AUTHOR]

The photochemical activation of carbon–hydrogen bonds by vanadium(V)–dioxo and vanadium(V)–oxo–peroxo diimine complexes is described. Reactions were carried out using a selection of organic substrates with C–H bond dissociation free energy values between 70 and 97 kcal mol−1. The ability to activate C–H bonds using vanadium(V)–dioxo and vanadium(V)–oxo–peroxo diimine complexes varies with different bond dissociation free energy. Compounds with weaker C–H bonds are oxidized in minutes, rather than in days for thermal oxidations by the corresponding complexes. Dioxygen is necessary for substrate consumption, which suggests that the electronically excited V complexes are radical reaction initiators via H-atom abstraction from the organic substrate. [ABSTRACT FROM AUTHOR]

The article describes a number of concerted proton-electron transfer (CPET) reactions of ascorbates in MeCN, which reveal an unusual solvent dependence of the O-H bond dissociation free energy. It concludes that ascorbyl radical is readily generated from the corresponding ascorbate by phenoxyl and nitroxyl radicals.

We combine experimental and computational methods to address the anomalous kinetics of long-range electron transfer (ET) in mutants of Pseudomonas aeruginosa azurin. ET rates and driving forces for wild type (WT) and three N47X mutants (X = L, S, and D) of Ru(2,20-bipyridine)2 (imidazole)(His83) azurin are reported. An enhanced ET rate for the N47L mutant suggests either an increase of the donor–acceptor (DA) electronic coupling or a decrease in the reorganization energy for the reaction. The underlying atomistic features are investigated using a recently developed nonadiabatic molecular dynamics method to simulate ET in each of the azurin mutants, revealing unexpected aspects of DA electronic coupling. In particular, WT azurin and all studied mutants exhibit more DA compression during ET (>2 Å ) than previously recognized. Moreover, it is found that DA compression involves an extended network of hydrogen bonds, the fluctuations of which gate the ET reaction, such that DA compression is facilitated by transiently rupturing hydrogen bonds. It is found that the N47L mutant intrinsically disrupts this hydrogen-bond network, enabling particularly facile DA compression. This work, which reveals the surprisingly fluctional nature of ET in azurin, suggests that hydrogenbond networks can modulate the efficiency of long-range biological ET. [ABSTRACT FROM AUTHOR]

Lignolytic peroxidases use an electron transfer (ET) pathway that involves amino acid-mediated substrate oxidation at the surface of the protein rather than at an embedded heme site. In many of these peroxidases, redox catalysis takes place at a substrate accessible tyrosine or tryptophan (Trp) amino acid. Here, we describe new mutants of cytochrome c peroxidase (CcP) that were designed to incorporate a Trp-based “wire” that can move oxidizing equivalents from the heme to the protein surface. Three mutant CcP proteins were expressed and characterized: A193W, Y229W, and A193W/Y229W. These mutants can oxidize veratryl alcohol substrate with turnover numbers greater than wild type CcP using H2O2 as an oxidant. The A193W/Y229W mutant is the most active. However, the reactivity is still less than typical lignin peroxidases at pH 8. The redox reactivity of these proteins is analysed using semiclassical electron transfer theory. An electron hopping mechanism is possible for A193W/Y229W mutant. These data suggest that artificial chains of aromatic amino acids can support hole transfer from embedded sites to protein surfaces for catalytic redox reactions. [ABSTRACT FROM AUTHOR]

The development and implementation of technology that can capture and transform carbon dioxide (CO2) is of ongoing interest. To that end, the integration of molecular electrocatalysts into devices is appealing because of the desirable features of molecules, such as the ability to modify active sites. Here, we explore how the identity of the aliphatic group in 1,4,8,11,15,18,22,25-octaalkoxyphthalocyanine cobalt(II) affects the catalytic behavior for heterogeneous CO2 reduction electrocatalysis. The alkyl R-groups correspond to n-butoxy, sec-butoxy, and 2-ethylhexoxy. All of the catalysts are soluble in organic solvents and are readily solution-processed. However, the larger 2-ethylhexoxy group showed solution aggregation behavior at concentrations ≥1 mM, and it was, in general, an inferior catalyst. The other two catalysts show comparable maximum currents, but the octa sec-butoxy-bearing catalyst showed larger CO2 reduction rate constants based on foot-of-the-wave analyses. This behavior is hypothesized to be due to the ability of the sec-butoxy groups to eliminate the ability of the alkoxy oxygen to block Co Sites via ligation. CO2 reduction activity is rationalized based on solid-state structures. Cobalt(II) phthalocyanine and its derivatives are known to be good CO2 reduction catalysts, but the results from this work suggest that straightforward incorporation of bulky groups can improve the processability and per site activity by discouraging aggregation. [ABSTRACT FROM AUTHOR]

The reduction of CO 2 to CO is an ongoing chemical challenge of great interest for the development of renewable and sustainable technologies. Coordination complexes of rhenium(I) are widely known as CO 2 reduction electrocatalysts, with emphasis on complexes bearing 2,2′-bipyridine (bpy) ligands. Recent research efforts have focused on incorporation of these catalysts into solid, electroactive supports, which can be challenging due to the requirement for synthetic modification to bpy ligands. Development of related ligand sets with modular syntheses is therefore an attractive goal. We investigated electrocatalytic CO 2 reduction using ReCl(CO) 3 (N-N) complexes, where N-N is 2-(2′-pyridyl)imidazole (PyIm), 2-(2′-pyridyl)benzimidazole (PyBIm), 2-(2′-quinolyl)imidazole (QuIm), or 2-(2′-quinolyl)benzimidazole (QuBIm) ligands. In CO 2 -saturated MeCN solutions, cyclic voltammograms of the Re-QuBIm complex showed current enhancement at a peak potential of −2.01 V vs. Cp 2 Fe +/0 . The catalytic current was stable upon repeated cycling. Re-QuBIm has an overpotential ∼200 mV lower than related Re-bpy catalysts, but also is kinetically slower. The redox reactivity of each complex can be correlated to electronic parameters of the N-N chelating ligands. These results suggest that modular reduction potential tuning of CO 2 reduction catalysts is possible, but associated penalties to activity are important considerations. [ABSTRACT FROM AUTHOR]

Appending of ferrocene (Fc) to biologically-active organic backbones can generate novel multi-functional species for targeting bacteria and cancer. In this work Fc was linked to coumarin and anthraquinone with the goal of harnessing the redox-active Fc centre to generate new compounds that exhibit cytoxicity through the generation of toxic reactive oxygen species (ROS). A Cu(I)-catalyzed azide–alkyne cycloaddition "click" reaction was used to connect the organic and Fc components via a triazole linker. Cyclic voltammetry shows that the Fc potentials are suitable for oxidation by biological hydrogen peroxide to give reactive ferrocenium (Fc+) species, which can then generate hydroxyl radicals. The ability of the compounds to generate hydroxyl radicals in the presence of hydrogen peroxide was shown directly using EPR spin-trapping experiments. Furthermore, in vitro studies in MCF-7 breast cancer cells show significant increases in ROS following incubation with the Fc-functionalized compounds. Screening for antibacterial activity produced negative results for all of the Fc compounds, consitent with low levels of hydrogen peroxide typically found in bacteria. By contrast, Fc-coumarin showed cytotoxicity against A549 lung cancer and SKOV3 ovarian cancer cell lines, whereas the parent compound was inactive. This is consistent both with the cytoxic potential of the Fc group and the elevated hydrogen peroxide levels found in many cancers. Interestingly, the anthraquinone compounds showed the opposite effect with the parent compounds showing modest activity against A549 cells, but the Fc compounds being inactive. This demonstrates other potential negative impacts of including Fc, such as significantly increased lipophilicity. [ABSTRACT FROM AUTHOR]

Short-range, non-covalent interactions between amino acid residues determine protein structures and contribute to protein functions in diverse ways. The interactions of the thioether of methionine with the aromatic rings of tyrosine, tryptophan, and/or phenylalanine has long been discussed and such interactions are favorable on the order of 1–3 kcal mol−1. Here, we carry out a new bioinformatics survey of known protein structures where we assay the propensity of three aromatic residues to localize around the [-CH2-S-CH3] of methionine. We term these groups "3-bridge clusters". A dataset consisting of 33,819 proteins with less than 90% sequence identity was analyzed and such clusters were found in 4093 structures (or 12% of the non-redundant dataset). All sub-classes of enzymes were represented. A 3D coordinate analysis shows that most aromatic groups localize near the CH2 and CH3 of methionine. Quantum chemical calculations support that the 3-bridge clusters involve a network of interactions that involve the Met-S, Met-CH2, Met-CH3, and the π systems of nearby aromatic amino acid residues. Selected examples of proposed functions of 3-bridge clusters are discussed. [ABSTRACT FROM AUTHOR]

We show that molecular catalysts for fuel-forming reactions can be immobilized on graphitic carbon electrode surfaces via noncovalent interactions. A pyrene-appended bipyridine ligand (P) serves as the linker between each complex and the surface. Immobilization of a rhodium proton-reduction catalyst, [Cp"Rh(P)Cl]Cl (1), and a rhenium CO2-reduction catalyst, Re(P)-(CO)3Cl (2), afford electrocatalytically active assemblies. X-ray photoelectron spectroscopy and electrochemistry confirm catalyst immobilization. Reduction of 1 in the presence of p-toluenesulfonic acid results in catalytic H2 production, while reduction of 2 in the presence of CO2results in catalytic CO production [ABSTRACT FROM AUTHOR]

Electrocatalytic CO2 reduction in water using a series of chlorotricarbonylrhenium(I) diimine complexes deposited on pyrolytic graphite electrodes is described. Two known CO2 reduction catalysts (with diimine = 4,4′-di-tert-butyl-2,2′-bipyridine or 2-(2′-quinolyl)benzimidazole), that are highly active in organic solvent, proved to be only weakly active in water. In contrast, Cl(CO)3Re(L) complexes with tridentate nitrogen-containing ligands (L = 4,4′,4′′-tri-tert-butyl-2,2′:6′,2′′-terpyridine or 2,6-bis(2-benzimidazolyl)pyridine) were better CO2 reduction catalysts. In those Cl(CO)3Re(L) complexes, only two N-atoms of the ligand are coordinated to the rhenium, leaving the third arm of the ligands to support activated, CO2-bound intermediates. The 2,6-bis(2-pyridyl)pyridine (terpy) complex was the most active, with substantial activity at alkaline pH. [ABSTRACT FROM AUTHOR]

The p53 protein plays a major role in cancer prevention, and over 50 % of cancer diagnoses can be attributed to p53 malfunction. The common p53 mutation Y220C causes local protein unfolding, aggregation, and can result in a loss of Zn in the DNA‐binding domain. Structural analysis has shown that this mutant creates a surface site that can be stabilized using small molecules, and herein a multifunctional approach to restore function to p53‐Y220C is reported. A series of compounds has been designed that contain iodinated phenols aimed for interaction and stabilization of the p53‐Y220C surface cavity, and Zn‐binding fragments for metallochaperone activity. Their Zn‐binding affinity was characterized using spectroscopic methods and demonstrate the ability of compounds L4 and L5 to increase intracellular levels of Zn2+ in a p53‐Y220C‐mutant cell line. The in vitro cytotoxicity of our compounds was initially screened by the National Cancer Institute (NCI‐60), followed by testing in three stomach cancer cell lines with varying p53 status', including AGS (WTp53), MKN1 (V143A), and NUGC3 (Y220C). Our most promising ligand, L5, is nearly 3‐fold more cytotoxic than cisplatin in a large number of cell lines. The impressive cytotoxicity of L5 is further maintained in a NUGC3 3D spheroid model. L5 also induces Y220C‐specific apoptosis in a cleaved caspase‐3 assay, reduces levels of unfolded mutant p53, and recovers p53 transcriptional function in the NUGC3 cell line. These results show that these multifunctional scaffolds have the potential to restore wild‐type function in mutant p53‐Y220C. In a bind: A series of compounds has been designed that contain iodinated phenols aimed for interaction and stabilization of the p53‐Y220C surface cavity, and Zn‐binding fragments for metallochaperone activity. Their Zn‐binding affinity was characterized using spectroscopic methods and demonstrate the ability of compounds L4 and L5 to increase intracellular levels of Zn2+ in a p53‐Y220C‐mutant cell line. Results from in vitro cytotoxic tests show that these multifunctional scaffolds have the potential to restore wild‐type function in mutant p53‐Y220C. [ABSTRACT FROM AUTHOR]

Rapid and low overpotential oxidation of water to dioxygen remains a key hurdle for storage of solar energy. Here, we address this issue by demonstrating that deprotonation of 2-(2′-pyridyl)-imidazole (pimH)-ligated copper complexes promotes water oxidation at low overpotential and low catalyst loading. This improves upon other work on homogeneous copper-based water oxidation catalysts, which are highly active, but limited by high overpotentials. EPR and UV-vis spectroscopic evaluation of catalyst speciation shows that at pH ≥ 12 coordinated pimH is deprotonated and a bis(hydroxide) Cu2+ active catalyst forms. Rapid electrochemical water oxidation (35 s−1, 0.85 V onset potential) was observed with 150 μM catalyst. These results demonstrate that catalytic water oxidation potentials can be shifted by hundreds of mV in homogeneous metal catalysts bearing an ionisable imidazole ligand. [ABSTRACT FROM AUTHOR]

The Ru(III) complexes indazolium [trans-RuCl4(1H-indazole)2] (KP1019) and sodium [trans-RuCl4(1H-indazole)2] (NKP-1339) are leading candidates for the next generation of metal-based chemotherapeutics. Trifluoromethyl derivatives of these compounds and their imidazole and pyridine analogues were synthesized to probe the effect of ligand lipophilicity on the pharmacological properties of these types of complexes. Addition of CF3 groups also provided a spectroscopic handle for 19F NMR studies of ligand exchange processes and protein interactions. The lipophilicities of the CF3-functionalized compounds and their unsubstituted parent complexes were quantified by the shake-flask method to give the distribution coefficient Dat pH 7.4 (log D7.4). The solution behavior of the CF3-functionalized complexes was characterized in phosphate-buffered saline (PBS) using 19F NMR, electron paramagnetic resonance (EPR), and UV-vis spectroscopies. These techniques, along with fluorescence competition experiments, were also used to characterize interactions with human serum albumin (HSA). From these studies it was determined that increased lipophilicity correlates with reduced solubility in PBS but enhancement of noncoordinate interactions with hydrophobic domains of HSA. These protein interactions improve the solubility of the complexes and inhibit the formation of oligomeric species. EPR measurements also demonstrated the formation of HSA-coordinated species with longer incubation. 19F NMR spectra show that the trifluoromethyl complexes release axial ligands in PBS and in the presence of HSA. In vitro testing showed that the most lipophilic complexes had the greatest cytotoxic activity. Addition of CF3 groups enhances the activity of the indazole complex against A549 nonsmall cell lung carcinoma cells. Furthermore, in the case of the pyridine complexes, the parent compound was inactive against the HT-29 human colon carcinoma cell line but showed strong cytotoxicity with CF3 functionalization. Overall, these studies demonstrate that lipophilicity may be a determining factor in the anticancer activity and pharmacological behavior of these types of Ru(III) complexes. [ABSTRACT FROM AUTHOR]

Efficient catalysis of the oxygen reduction reaction (ORR) is of central importance to function in fuel cells. Metalloproteins, such as laccase (Cu) or cytochrome c oxidase (Cu/Fe–heme) carry out the 4H + /4e − reduction quite efficiently, but using large, complex protein frameworks. Smaller heme proteins also can carry out ORR, but less efficiently. To gain greater insight into features that promote efficient ORR, we expressed, characterized, and investigated the electrochemical behavior of six new mutants of cytochrome c 552 from Thermus thermophilus : V49S/M69A, V49T/M69A, L29D/V49S/M69A, P27A/P28A/L29D/V49S/M69A, and P27A/P28A/L29D/V49T/M69A. Mutation to V49 causes only minor shifts to Fe III/II reduction potentials ( E °′), but introduction of Ser provides a hydrogen bond donor that slightly enhances oxygen reduction activity. Mutation of L29 to D induces small shifts in heme optical spectra, but not to E °′ (within experimental error). Replacement of P27 and P28 with A in both positions induces a − 50 mV shift in E °′, again with small changes to the optical spectra. Both the optical spectra and reduction potentials have signatures consistent with peroxidase enzymes. The V49S and V49T mutations have the largest impact of ORR catalysis, suggesting that increased electron density at the Fe site does not improve O 2 reduction chemistry. [ABSTRACT FROM AUTHOR]

A series of novel ferrocene (Fc) functionalized Ru(III) complexes was synthesized and characterized. These compounds are derivatives of the anti-metastatic Ru(III) complex imidazolium [trans-RuCl4(1H-imidazole) (DMSO-S)] (NAMI-A) and are derived from its pyridine analogue (NAMI-Pyr), with direct coupling of Fc to pyridine at the 4 or 3 positions, or at the 4 position via a two-carbon linker, which is either unsaturated (vinyl) or saturated (ethyl). Electron paramagnetic resonance (EPR) and UV-vis spectroscopic studies of the ligand exchange processes of the compounds in phosphate buffered saline (PBS) report similar solution behavior to NAMI-Pyr. However, the complex with Fc substitution at the 3 position of the coordinated pyridine shows greater solution stability, through resistance to the formation of oligomeric species. Further EPR studies of the complexes with human serum albumin (hsA) indicate that the Fc groups enhance noncoordinate interactions with the protein and help to inhibit the formation of protein-coordinated species, suggesting the potential for enhanced bioavailability. Cyclic voltammetry measurements demonstrate that the Fc groups modestly reduce the reduction potential of the Ru(III) center as compared to NAMI-Pyr, while the reduction potentials of the Fc moieties of the four compounds vary by 217 mV, with the longer linkers giving significantly lower values of E1/2. EPR spectra of the compounds with 2-carbon linkers show the formation of a high-spin Fe(III) species (S = 5/2) in PBS with a distinctive signal at g = 4.3, demonstrating oxidation of the Fe(II) ferrocene center and likely reflecting degradation products. Density functional theory calculations and paramagnetic ¹H NMR describe delocalization of spin density onto the ligands and indicate that the vinyl linker could be a potential pathway for electron transfer between the Ru and Fe centers. In the case of the ethyl linker, electron transfer is suggested to occur via an indirect mechanism enabled by the greater flexibility of the ligand. In vitro assays with the SW480 cell line reveal cytotoxicity induced by the ruthenium ferrocenylpyridine complexes that is at least an order of magnitude higher than the unfunctionalized complex, NAMI-Pyr. Furthermore, migration studies with LNCaP cells reveal that Fc functionalization does not reduce the ability of the compounds to inhibit cell motility. Overall, these studies demonstrate that NAMI-A-type compounds can be functionalized with redox-active ligands to produce both cytotoxic and anti-metastatic activity. [ABSTRACT FROM AUTHOR]

Oxygen reduction in acidic aqueous solution mediated by a series of asymmetric iron (III)-tetra(aryl)porphyrins adsorbed to basal- and edge- plane graphite electrodes is investigated. The asymmetric iron porphyrin systems bear phenyl groups at three meso positions and either a 2-pyridyl, a 2-benzoic acid, or a 2-hydroxyphenyl group at the remaining meso position. The presence of the three unmodified phenyl groups makes the compounds insoluble in water, enabling catalyst retention during electrochemical experiments. Resonance Raman data demonstrate that catalyst layers are maintained, but can undergo modification after prolonged catalysis in the presence of O2. The introduction of a single proton relay group at the fourth meso position makes the asymmetric iron porphyrins markedly more robust catalysts; these molecules support higher sustained current densities than the parent iron tetraphenylporphyrin. Iron porphyrins bearing a 2-pyridyl group are the most active catalysts and operate at stable current densities ≥1 mA cm−2 for over 5 h. Comparative analysis of the catalysts with different proton relays also is reported. [ABSTRACT FROM AUTHOR]

Oxygen-atom transfer reactions of metalloporphyrin species play an important role in biochemical and synthetic oxidation reactions. An emerging theme in this chemistry is that spin-state changes can play important roles, and a 'two-state' reactivity model has been extensively applied especially in iron porphyrin systems. Herein we explore the gas-phase oxygen-atom transfer chemistry of meso-tetrakis(pentafluorophenyl)porphyrin (TPFPP) chromium complexes, as well as some other tetradentate macrocyclic ligands. Electrospray ionization in concert with Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry has been used to characterize and observe reactivity of the ionic species [(TPFPP)CrIII]+ (1) and [(TPFPP)CrVO]+ (2). These are attractive systems to examine the effects of spin-state change on oxygen-atom transfer because the d1 CrV species are doublets, while the CrIII complexes have quartet ground states with high-lying doublet excited states. In the gas phase, [(TPFPP)CrIII]+ forms adducts with a variety of neutral donors, but O-atom transfer is only observed for NO2. Pyridine N-oxide adducts of 1 do yield 2 upon collision-induced dissociation (CID), but the ethylene oxide, DMSO, and TEMPO analogues do not. [(TPFPP)CrVO]+ is shown by its reactivity and by CID experiments to be a terminal metal-oxo with a single, vacant coordination site. It also displays limited reaction chemistry, being deoxygenated only by the very potent reductant P(OMe)3. In general, [(TPFPP)CrVO]+ species are much less reactive than the Fe and Mn analogues. Thermochemical analysis of the reactions points toward the involvement of spin issues in the lower observed reactivity of the chromium complexes. [ABSTRACT FROM AUTHOR]