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The low-valent Ni–Ni-bonded compound [(NiIL·–)2] (1, L= [(2,6-iPr2C6H3)NC(Me)]2) reacts with a series of multicyclic polyenes through different redox processes, affording seven heteroleptic complexes (2–8) containing nickel, α-diimine L, and polyene (or polyenyl) ligands, where all three components exhibit variable oxidation states. The reaction of 1with 6-(dimethylamino)fulvene or 6,6-dimethylfulvene led to the reductive dimerization of two fulvene molecules, yielding the dinuclear complexes 2and 3with a bridging bis-Cp ligand. In contrast, similar reactions with 6,6-diphenylfulvene or pentamethylcyclopentadiene (C5Me5H) only gave the adducts [LNi(η4-6,6-diphenylfulvene)] (4) or [(L·–)Ni(η4-C5Me5H)] (5) with a neutral polyene molecule. However, the two complexes have different oxidation levels of the nickel center and ligand L, depending on the electronic property of the substrate. By using biphenylene, oxidative addition of a strained C–C bond to nickel occurred to form the biphenyl metallacycle [LNi(μ2-Ph2)] (6). Furthermore, the reaction of 1with acenaphthylene or C60afforded complexes [LNi(η2-acenaphthylene)] (7) and [LNi(η2-C60)] (8) featuring an η2-bonded neutral polyene. The results provide evidence of the facile electron transfer between the metal and ligands so that the nickel center can adjust its basicity to coordinate effectively with polyene substrates of different π-acidity.

The influences of biological, chemical, and flow processes on soil structure through microbially induced carbonate precipitation (MICP) are not yet fully understood. In this study, we use a multi-level thresholding segmentation algorithm, genetic algorithm (GA) enhanced Kapur entropy (KE) (GAE-KE), to accomplish quantitative characterization of sandy soil structure altered by MICP cementation. A sandy soil sample was treated using MICP method and scanned by the synchrotron radiation (SR) micro-CT with a resolution of 6.5 μm. After validation, tri-level thresholding segmentation using GAE-KE successfully separated the precipitated calcium carbonate crystals from sand particles and pores. The spatial distributions of porosity, pore structure parameters, and flow characteristics were calculated for quantitative characterization. The results offer pore-scale insights into the MICP treatment effect, and the quantitative understanding confirms the feasibility of the GAE-KE multi-level thresholding segmentation algorithm.

Odd-electron bonds, i.e., the two-center, three-electron (2c/3e), or one-electron (2c/1e) bonds, have attracted tremendous interest owing to their novel bonding nature and radical properties. Herein, complex [K(THF)6][LSn:···Sn:L] (1), featuring the first and unsupported 2c/1e Sn···Sn σ-bond with a long distance (3.2155(9) Å), was synthesized by reduction of stannylene [LSn:] (L = N,N-dpp-o-phenylene diamide) with KC8. The one-electron Sn–Sn bond in 1was confirmed by the crystal structure, DFT calculations, EPR spectroscopy, and reactivity studies. This compound can be viewed as a stabilized radical by delocalizing to two metal centers and can readily mediate radical reactions such as C–C coupling of benzaldehyde.

Accomplishments of enhanced activity and durability are a major concern in the design of catalysts for acidic water oxidation. To date, most studied supported metal catalysts undergo fast degradation in strongly acidic and oxidative environments due to improper controlling of the interface stability caused by their lattice mismatches. Here, we evaluate the activity–stability trends of in situ crystallized antimony-doped tin oxide (Sb-SnO2)@RuOx(Sb-SnO2@RuOx) heterostructure nanosheets (NSs) for acidic water oxidation. The catalyst prepared by atomic layer deposition of a conformal Ru film on antimony-doped tin sulfide (Sb-SnS2) NSs followed by heat treatment highlights comparable activity but longer stability than that of the ex situ catalyst (where Ru was deposited on Sb-SnO2followed by heating). Air calcination for in situ crystallization allows the formation of hierarchical mesoporous Sb-SnO2NSs from as-prepared Sb-SnS2NSs and parallel in situ transformation from Ru to RuOx, resulting in a compact heterostructure. The significance of this approach significantly resists corrosive dissolution, which is justified by the enhanced oxygen evolution reaction (OER) stability of the catalyst compared to most of the state-of-the-art ruthenium-based catalysts including Carbon@RuOx(which shows ∼10 times higher dissolution) as well as Sb-SnO2@Com. RuOxand Com. RuO2. This study demonstrates the controlled interface stability of heterostructure catalysts toward enhancing OER activity and stability.

The catalytic transformation of N2to NH3by transition metal complexes is of great interest and importance but has remained a challenge to date. Despite the essential role of vanadium in biological N2fixation, well-defined vanadium complexes that can catalyze the conversion of N2to NH3are scarce. In particular, a V(NxHy) intermediate derived from proton/electron transfer reactions of coordinated N2remains unknown. Here, we report a dinitrogen-bridged divanadium complex bearing POCOP (2,6-(tBu2PO)2-C6H3) pincer and aryloxy ligands, which can serve as a catalyst for the reduction of N2to NH3and N2H4. Low-temperature protonation and reduction of the dinitrogen complex afforded the first structurally characterized neutral metal hydrazido(2−) species ([V]═NNH2), which mediated 15N2conversion to 15NH3, indicating that it is a plausible intermediate of the catalysis. DFT calculations showed that the vanadium hydrazido complex [V]═NNH2possessed a N–H bond dissociation free energy (BDFEN–H) of as high as 59.1 kcal/mol. The protonation of a vanadium amide complex ([V]–NH2) with [Ph2NH2][OTf] resulted in the release of NH3and the formation of a vanadium triflate complex, which upon reduction under N2afforded the vanadium dinitrogen complex. These transformations model the final steps of a vanadium-catalyzed N2reduction cycle. Both experimental and theoretical studies suggest that the catalytic reaction may proceed via a distal pathway to liberate NH3. These findings provide unprecedented insights into the mechanism of N2reduction related to FeV nitrogenase.

Graphical Abstract:

Objective:We explore the pharmacodynamic targets of kaempferol in treating osteoporosis using transcriptomics and animal experiment. Methods:Firstly, we constructed an ovariectomized rat model (OVX). The anti-osteoporosis effect of kaempferol was evaluated by bone mineral density (BMD) and hematoxylin-eosin staining comprehensively. Moreover, differential genes between groups were screened by RNA sequencing technology (RNA-seq) for transcriptomics and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways enrichment analysis were performed. Finally, partial results of transcriptomics were verified to detect the expression of the relevant gene expression by immunohistochemistry. Results:The pharmacodynamic findings indicated that the administration of kaempferol resulted in an elevation in BMD (P< .01) and a notable enhancement in tibia microstructural indices in the experimental rats (P< .01). The transcriptomic analysis revealed that NTN1, LTBP4, GSN, and EBF1 were identified as the principal targets for therapeutic intervention in osteoporosis. The results of animal experiments showed that kaempferol promoted osteogenesis and inhibited bone resorption by downregulating the protein expression of NTN1, LTBP4, GSN, and EBF1 (P< .01). Conclusion:Kaempferol enhances BMD levels, retards tibial bone loss with structural deterioration in OVX model rats, and promotes bone formation while curbing bone resorption through NTN1, LTBP4, GSN, and EBF1 protein down-regulation.

SHP2 is a nonreceptor protein tyrosine phosphatase encoded by the PTPN11gene and is involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also plays an important role in the programed cell death pathway (PD-1/PD-L1). As an oncoprotein as well as a potential immunomodulator, controlling SHP2 activity is of high therapeutic interest. As part of our comprehensive program targeting SHP2, we identified multiple allosteric binding modes of inhibition and optimized numerous chemical scaffolds in parallel. In this drug annotation report, we detail the identification and optimization of the pyrazine class of allosteric SHP2 inhibitors. Structure and property based drug design enabled the identification of protein–ligand interactions, potent cellular inhibition, control of physicochemical, pharmaceutical and selectivity properties, and potent in vivoantitumor activity. These studies culminated in the discovery of TNO155, (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (1), a highly potent, selective, orally efficacious, and first-in-class SHP2 inhibitor currently in clinical trials for cancer.

Neutral N-pyrazolyl radicals [3,5-R2pz]•as reactive intermediates were generated by one-electron oxidization of the corresponding 3,5-disubstituted pyrazolato anions [3,5-R2pz]−(R = tBu, Ph) with BiCl3and trapped by the use of 5,5-dimethyl-1-pyrroline-N-oxide as a spin trap, which was confirmed by electron paramagnetic resonance spectral analysis. With dimerization of the postulated pyrazolato low-valent BiIIradical species, two novel paddlewheel pyrazolatodibismuthanes [L2(Bi–Bi)L2] [L = η1,η1-3,5-R2pz; R = tBu (5α, 5β, and 5γ), Ph (6)] were isolated and structurally characterized.

A novel 2,6-naphthyridine was identified by high throughput screen (HTS) as a dual protein kinase C/D (PKC/PKD) inhibitor. PKD inhibition in the heart was proposed as a potential antihypertrophic mechanism with application as a heart failure therapy. As PKC was previously identified as the immediate upstream activator of PKD, PKD vs PKC selectivity was essential to understand the effect of PKD inhibition in models of cardiac hypertrophy and heart failure. The present study describes the modification of the HTS hit to a series of prototype pan-PKD inhibitors with routine 1000-fold PKD vs PKC selectivity. Example compounds inhibited PKD activity in vitro, in cells, and in vivo following oral administration. Their effects on heart morphology and function are discussed herein.

The multifunctionalization of unactivated cyclic ketones was developed via an electrochemically intermolecular α-amination under metal-free conditions. The reaction can be carried out smoothly with a broad scope of the aromatic amines substrates under mild conditions, affording a variety of α-enaminones with good to excellent yields in one step.

The life cycle environmental impacts of the new model radial passenger vehicle tire product was evaluated and compared. the silicon dioxide was added to replace part of the carbon black as filler, with its previous model tire product. The study covers all relevant life cycle stages: from the acquisition of raw materials to the production, use, and end-of-life. The data collected onsite in 2014 by one of the largest Chinese tire companies were used in the assessment. The evaluation is presented in terms of individual impact category according to the CML model. Five impact categories (i.e., global warming potential (GWP), acidification potential (AP), photochemical oxidant creation potential (POCP), eutrophication potential (EP), and human toxicity potential (HTP)) were considered. The research was conducted in accordance with the ISO 14040/14044 standards. The results showed that In all the five impact categories, new model tire product is lower than the previous model in the whole life cycle. It is mostly due to the reduction of the fuel consumption during the use stage, which resulted in replacing part of the carbon black with silicon dioxide. Fuel (gasoline) consumption represents an important contribution to most impact categories, including the GWP, AP, POCP, and EP, during the use stage. Vehicle fuel consumption and its proportion consumed by the tires during the use stage are key factors that contribute to environmental impact during tire life time. The largest contributor to the HTP category is raw material acquisition, mainly because of the impact of the production of organic chemicals. During the raw material acquisition stage, natural rubber, synthetic rubber, carbon black, and organic chemicals represent the largest contribution to the environmental impact categories, which could be mitigated by reducing the use of raw materials, replacing the aromatic oil with environmental oil in the new model tire product.

Protein kinases are known for their highly conserved adenosine triphosphate (ATP)-binding site, rendering the discovery of selective inhibitors a major challenge. In theory, allosteric inhibitors can achieve high selectivity by targeting less conserved regions of the kinases, often with an added benefit of retaining efficacy under high physiological ATP concentration. Although often overlooked in favor of ATP-site directed approaches, performing a screen at high ATP concentration or stringent hit triaging with high ATP concentration offers conceptually simple methods of identifying inhibitors that bind outside the ATP pocket. Here, we applied the latter approach to the With-No-Lysine (K) (WNK) kinases to discover lead molecules for a next-generation antihypertensive that requires a stringent safety profile. This strategy yielded several ATP noncompetitive WNK1–4 kinase inhibitors, the optimization of which enabled cocrystallization with WNK1, revealing an allosteric binding mode consistent with the observed exquisite specificity for WNK1–4 kinases. The optimized compound inhibited rubidium uptake by sodium chloride cotransporter 1 (NKCC1) in HT29 cells, consistent with the reported physiology of WNK kinases in renal electrolyte handling.

One of the central questions in the characterization of enzyme inhibitors is determining the mode of inhibition (MOI). Classically, this is done with a number of low-throughput methods in which inhibition models are fitted to the data. The ability to rapidly characterize the MOI for inhibitors arising from high-throughput screening in which hundreds to thousands of primary inhibitors may need to be characterized would greatly help in lead selection efforts. Here we describe a novel method for determining the MOI of a compound without the need for curve fitting of the enzyme inhibition data. We provide experimental data to demonstrate the utility of this new high-throughput MOI classification method based on nonparametric analysis of the activity derived from a small matrix of substrate and inhibitor concentrations (e.g., from a 4S× 4Imatrix). Lists of inhibitors from four different enzyme assays are studied, and the results are compared with the previously described IC50-shift method for MOI classification. The MOI results from this method are in good agreement with the known MOI and compare favorably with those from the IC50-shift method. In addition, we discuss some advantages and limitations of the method and provide recommendations for utilization of this MOI classification method.

A metal-free electrophotochemical C(sp3)-H arylation was developed under mild conditions. This method enables a switchable synthesis of diaryl alcohols and diaryl alkanes from inactive benzylic carbons. More importantly, a cheap and safe mediator N-chlorosuccinimide (NCS) was developed, which was employed for the hydrogen atom transfer (HAT) process of the benzylic C–H bond. In addition, this active radical was captured and identified by electron paramagnetic resonance (EPR).

SHP099, a selective inhibitor of signalling meditator SHP2 with drug-like properties, has an allosteric mechanism of action whereby it stabilizes SHP2 in an auto-inhibited conformation, and suppresses RAS–ERK signalling and proliferation in receptor-tyrosine-kinase-driven cancer cell lines and mouse tumour xenograft models.