Is the ruthenium analogue of compound I of cytochrome p450 an efficient oxidant? A theoretical investigation of the methane hydroxylation reaction

High-valent metal-oxo complexes catalyze C-H bond activation by oxygen insertion, with an efficiency that depends on the identity of the transition metal and its oxidation state. Our study uses density functional calculations and theoretical analysis to derive fundamental factors of catalytic activity, by comparison of a ruthenium-oxo catalyst with its iron-oxo analogue toward methane hydroxylation. The study focuses on the ruthenium analogue of the active species of the enzyme cytochrome P450, which is known to be among the most potent catalysts for C-H activation. The computed reaction pathways reveal one high-spin (HS) and two low-spin (LS) mechanisms, all nascent from the low-lying states of the ruthenium-oxo catalyst (Ogliaro, F.; de Visser, S. P.; Groves, J. T.; Shaik, S. Angew. Chem. Int. Ed. 2001, 40, 2874-2878). These mechanisms involve a bond activation phase, in which the transition states (TS's) appear as hydrogen abstraction species, followed by a C-O bond making phase, through a rebound of the methyl radical on the metal-hydroxo complex. However, while the HS mechanism has a significant rebound barrier, and hence a long lifetime of the radical intermediate, by contrast, the LS ones are effectively concerted with small barriers to rebound, if at all. Unlike the iron catalyst, the hydroxylation reaction for the ruthenium analogue is expected to follow largely a single-state reactivity on the LS surface, due to a very large rebound barrier of the HS process and to the more efficient spin crossover expected for ruthenium. As such, ruthenium-oxo catalysts (Groves, J. T.; Shalyaev, K.; Lee, J. In The Porphyrin Handbook; Biochemistry and Binding: Activation of Small Molecules, Vol. 4; Kadish, K. M., Smith, K. M., Guilard, R., Eds.; Academic Press: New York, 2000; pp 17-40) are expected to lead to more stereoselective hydroxylations compared with the corresponding iron-oxo reactions. It is reasoned that the ruthenium-oxo catalyst should have larger turnover numbers compared with the iron-oxo analogue, due to lesser production of suicidal side products that destroy the catalyst (Ortiz de Montellano, P. R.; Beilan, H. S.; Kunze, K. L.; Mico, B. A. J. Biol. Chem. 1981, 256, 4395-4399). The computations reveal also that the ruthenium complex is more electrophilic than its iron analogue, having lower hydrogen abstraction barriers. These reactivity features of the ruthenium-oxo system are analyzed and shown to originate from a key fundamental factor, namely, the strong 4d(Ru)-2p(O,N) overlaps, which produce high-lying pi(Ru-O), sigma(Ru-O), and sigma(Ru-N) orbitals and thereby to lead to a preference of ruthenium for higher-valent oxidation states with higher electrophilicity, for the effectively concerted LS hydroxylation mechanism, and for less suicidal complexes. As such, the ruthenium-oxo species is predicted to be a more robust catalyst than its iron-oxo analogue.     

Evolution of Surface Morphology with Introduction of Stacking Faults in Zeolites

This paper sets out to try to determine some of the nanoscopic details of template action in zeolites. The problem has been addressed by monitoring the effects of competitive templating using, in particular, atomic force microscopy and high‐resolution scanning electron microscopy. Using these techniques, it is possible to determine the subtle crystal growth changes that occur as a result of altering the concentration of these competitive templating agents. This work concerns the two important intergrowth systems MFI–MEL and FAU–EMT. It was found that some organic templating agents provide much greater structure‐directing specificity. So much so in the case of the MFI–MEL system that a 2 mol % doping with the highly specific tetrapropylammonium cation drastically changes the fundamental growth processes. Furthermore, the effect of template crowding is shown to reduce specificity. This work shows how extensive frustrated intergrowth structures can still be accommodated within a nominal zeolite single crystal.     

Microwave-assisted synthesis of 4-chloro-N-(naphthalen-1-ylmethyl)-5-(3-(piperazin-1-yl)phenoxy)thiophene-2-sulfonamide (B-355252): a new potentiator of Nerve Growth Factor (NGF)-induced neurite outgrowth

The synthesis of 4-chloro-N-(naphthalen-1-ylmethyl)-5-(3-(piperazin-1-yl)phenoxy)thiophene-2-sulfonamide (B-355252) using an MW-assisted nucleophilic aromatic substitution (S_NAr) reaction will be discussed. Utilization of this method allowed for the rapid generation of B-355252 heteroaryl ether core structure in the presence of cesium carbonate in dimethylformamide or tripotassium phosphate in N-methyl-2-pyrrolidone in 94% yield. Evaluation of B-355252 enhancement of nerve growth factor’s ability to stimulate neurite outgrowths was determined using NS-1 cells.     

Solvent-Free Synthesis of ZnO Nanoparticles by a Simple Thermal Decomposition Method

This paper reports on a novel processing route for producing ZnO nanoparticles by solid-state thermal decomposition of zinc(II) acetate nanostructures obtained by the sublimation of zinc(II) acetate powder. The sublimation process of the Zn(OAc)₂ powder was carried out in the temperature 150 °C for 2 h. In addition, nanoparticles of ZnO were obtained by solid-state thermal decomposition of the synthesized Zn(OAc)₂ nanostructures. The synthesized products were characterized by X-ray diffraction (XRD), scanning electron microscopy, transmission electron microscopy, photoluminescence spectroscopy, and energy dispersive X-ray spectroscopy. The sublimation process of the Zn(OAc)₂ powder was carried out within the range of 150–180 °C. The XRD studies indicated the production of pure hexagonal ZnO nanoparticles after thermal decomposition.     

Probing Reversible Chemistry in Coenzyme B12‐Dependent Ethanolamine Ammonia Lyase with Kinetic Isotope Effects

Coenzyme B₁₂‐dependent enzymes such as ethanolamine ammonia lyase have remarkable catalytic power and some unique properties that enable detailed analysis of the reaction chemistry and associated dynamics. By selectively deuterating the substrate (ethanolamine) and/or the β‐carbon of the 5′‐deoxyadenosyl moiety of the intrinsic coenzyme B₁₂, it was possible to experimentally probe both the forward and reverse hydrogen atom transfers between the 5′‐deoxyadenosyl radical and substrate during single‐turnover stopped‐flow measurements. These data are interpreted within the context of a kinetic model where the 5′‐deoxyadenosyl radical intermediate may be quasi‐stable and rearrangement of the substrate radical is essentially irreversible. Global fitting of these data allows estimation of the intrinsic rate constants associated with Co?C homolysis and initial H‐abstraction steps. In contrast to previous stopped‐flow studies, the apparent kinetic isotope effects are found to be relatively small.     

A Modular Synthesis of Conformationally Preorganised Extended β‐Strand Peptidomimetics

A promising strategy for mediating protein–protein interactions is the use of non‐peptidic mimics of secondary structural protein elements, such as the α‐helix. Recent work has expanded the scope of this approach by providing proof‐of‐principle scaffolds that are conformationally biased to mimic the projection of side‐chains from one face of another common secondary structural element—the β‐strand. Herein, we present a synthetic route that has key advantages over previous work: monomers bearing an amino acid side‐chain were pre‐formed before rapid assembly to peptidomimetics through a modular, iterative strategy. The resultant oligomers of alternating pyridyl and six‐membered cyclic ureas accurately reproduce a recognition domain of several amino acid residues of a β‐strand, demonstrated herein by mimicry of the i, i+2, i+4 and i+6 residues.     

Synthesis and structure‐optoelectronic property relationships of a series of PPV and SFTV derived polymers

Engineering of the highest occupied molecular orbital and lowest unoccupied molecular orbitals through synthetic chemical structural modification has been the most widely used method to tuning optoelectronic properties in conjugated polymers. The electronic, thermal, optical, and physical properties can be tuned and exploited for optimization of optoelectronic devices. Through copolymerization of donor and acceptor type conjugated monomers, the frontier orbitals of four polymers were tailored. Through this synthetic engineering, the relationship between structural features, frontier orbital tailoring, and changes in optoelectronic and physical properties are discussed. Spectroscopic, thermal, and electronic analysis of the polymers indicated that polymers containing carbazole monomer moieties gave overall improved optoelectronic properties, but higher band gaps (2.61 and 2.18 eV) in comparison to their phenyl‐ based counterparts. This result is attributed to the higher electron density of the carbazole than the terephthaldicarboxaldehyde, and the possible deviation from planarity in the polymer main chain due to possible steric hindrance of the branched substituents. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 2202–2213     

Precipitation and purification of uranium from rock phosphate

This study was carried-out to leach uranium from rock phosphate using sulphuric acid in the presence of potassium chlorate as an oxidant and to investigate the relative purity of different forms of yellow cakes produced with ammonia, magnesia and sodium hydroxide as precipitants, as well as purification of the products with TBP and matching its impurity levels with specifications of the commercial products. Alpha-particle spectrometry was used for determination of activity concentration of uranium isotopes in rock phosphate, resulting phosphoric acid, and in different forms of the yellow cake. Likewise, atomic absorption spectroscopy was used for determination of impurities. On the average, the equivalent mass concentration of uranium was 119.38 ± 79.66 ppm (rock phosphate) and 57.85 ± 20.46 ppm (phosphoric acid) with corresponding low percent of dissolution (48 %) which is considered low. The isotopic ratio (²³⁴U:²³⁸U) in all stages of hydrometallurgical process was not much different from unity indicating lack of fractionation. Upon comparing the levels of impurities in different form of crude yellow cakes, it was found that the lowest levels were measured in hydrated trioxide (UO₃·xH₂O). This implies that saturated magnesia is least aggressive relative to other precipitants and gives relatively pure crude cake. Therefore, it was used as an index to judge the relative purity of other forms of yellow cakes by taking the respective elemental ratios. The levels of impurities (Fe, Zn, Mn, Cu, Ni, Cd and Pb) in the purified yellow cake were found comparable with those specified for commercial products.     

The 2D IR responses of amide and carbonyl modes in water cannot be described by Gaussian frequency fluctuations

The two-dimensional (2D) IR spectral shapes seen for aqueous amide-I' or carbonyls having apparently single bands are not those predicted by Gaussian frequency fluctuations. Their population evolution exposes discrete distributions undergoing picosecond time scale exchange. The energy transfer to other modes provides a clear view of this underlying structure, which is largely attributed to exchanging water configurations. The results suggest new approaches to examine protein-bound water at the residue level.     

Rational design of thioamide peptides as selective inhibitors of cysteine protease cathepsin L

Aberrant levels of cathepsin L (Cts L), a ubiquitously expressed endosomal cysteine protease, have been implicated in many diseases such as cancer and diabetes. Significantly, Cts L has been identified as a potential target for the treatment of COVID-19 due to its recently unveiled critical role in SARS-CoV-2 entry into the host cells. However, there are currently no clinically approved specific inhibitors of Cts L, as it is often challenging to obtain specificity against the many highly homologous cathepsin family cysteine proteases. Peptide-based agents are often promising protease inhibitors as they offer high selectivity and potency, but unfortunately are subject to degradation in vivo. Thioamide substitution, a single-atom O-to-S modification in the peptide backbone, has been shown to improve the proteolytic stability of peptides addressing this issue. Utilizing this approach, we demonstrate herein that good peptidyl substrates can be converted into sub-micromolar inhibitors of Cts L by a single thioamide substitution in the peptide backbone. We have designed and scanned several thioamide stabilized peptide scaffolds, in which one peptide, R^S_1A, was stabilized against proteolysis by all five cathepsins (Cts L, Cts V, Cts K, Cts S, and Cts B) while inhibiting Cts L with >25-fold specificity against the other cathepsins. We further showed that this stabilized R^S_1A peptide could inhibit Cts L in human liver carcinoma lysates (IC₅₀ = 19 μM). Our study demonstrates that one can rationally design a stabilized, specific peptidyl protease inhibitor by strategic placement of a thioamide and reaffirms the place of this single-atom modification in the toolbox of peptide-based rational drug design.

Information on the effects of sidechain and backbone modification on the activity of cathepsin (Cts) L, V, K, S, and B was used to design a thioamide peptide that is inert to all Cts and selectively inhibits Cts L.