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Supramolecular host–guest systems are generally at thermodynamic equilibrium states or in kinetically trapped states. Herein, we demonstrate the concept of a chemical fuel-driven competitive host–g...

In this work, sewage sludge flocculated with ferrous sulfate (SFS) was treated by one-step pyrolysis and ZnCl2 activation to obtain magnetic Fe-containing carbon, which was used to remove elemental mercury (Hg0) from flue gas. When 30% ZnCl2 was added to SFS (names as SFS-30), sulfides, chloride, magnetic FexOy, as well as a suitable BET surface area were produced during pyrolysis. SFS-30 showed a maximum mercury removal efficiency of 96.1%. The presence of O2 and a low SO2 concentration enhanced Hg0 removal, while H2O vapor and a high concentration of SO2 inhibited it. The addition of ZnCl2 increased the BET surface area as well as the conversion of sulfate to sulfide, which were both beneficial for Hg0 removal. In addition, the generated magnetism during the pyrolysis process assisted in the recovery and utilization of SFS-30 in flue gas. After being magnetically separated from a mixture with fly ash, spent SFS-30 was thermally regenerated and recycled. After 8 Hg0 capture and regeneration cycles, the removal efficiency was not notably degraded, demonstrating that SFS-30 prepared by one-step pyrolysis with ZnCl2 activation can be used for Hg0 removal. The results of this study have guiding significance for practical engineering applications of this material.

By the bridging action of the 6-chloro-2-hydroxypyridine (Hchp) ligand and the terminal coordination role of the homochiral ligand, (-)/(+)-3-trifluoroacetyl camphor (l-Htfc/d-Htfc), a pair of enantiomerically pure dysprosium(III) dinuclear complexes, [Dy2(l-tfc)4(chp)2(MeOH)2] (l-1) and [Dy2(d-tfc)4(chp)2(MeOH)2] (d-1), was obtained. Their circular dichroism (CD) spectra verified their enantiomeric nature. Magnetic investigation indicated that they exhibit ferromagnetic interaction and good zero field single-molecule magnet (SMM) properties. The Ueff/k values of l-1 and d-1 at 0 Oe are 180.5 and 181.3 K, respectively, which are large values for homochiral Dy(III) SMMs. A reasonable explanation for the magnetic properties of l-1 and d-1 was supplied by ab initio calculations. Remarkably, magnetic circular dichroism (MCD) investigation revealed that the chiral Dy2 enantiomers show a strong magneto-optical Faraday effect at room temperature, suggesting potential applications in magneto-optical devices.

Xylan-based films have great potential to replace petroleum-based polymers used for packaging and coatings due to their excellent biocompatibility, biodegradability, and good gas barrier properties. However, fabricating a xylan-based film with flexible, transparent, water-proof, and excellent mechanical properties is an enormous challenge. Herein, we manufactured a series of degradable films with adjustable properties via solution-casting using a water-soluble xylan derivative. This is the first report of a pure xylan-based film with high performance, requiring no additives. The tensile strength of the xylan-based film could be controlled by adjusting the aldehyde content, which varied from 105.0 to 132.6 MPa. The smallest initial water contact angle of the xylan-based films is 93.26°, indicating that these films are hydrophobic. This work shows a simple and viable route toward manufacturing xylan-based films with high tensile strength, flexibility, and transparency, which can be used for packaging materials and coatings.

Background: Mezlocillin is off-label used for the treatment of respiratory infections in children. Therapeutic Drug Monitoring (TDM) data are also limited in children. A sensitive Liquid chromatography- tandem mass spectrometry (LC–MS/MS) method adapted to children was developed and validated for the determination of mezlocillin plasma concentration in the present study. Methods: Mezlocillin, extracted from a volume of 50 μL plasma using acetonitrile, was analyzed on an online LC-MS/MS system with an Agilent 1290 Infinity UHPLC (Agilent Technologies, CA, USA) coupled to an AB SCIEX QTRAP 6500PLUS MS/MS (AB Sciex, Framingham, MA, USA) with ceftiofur as an internal standard. HPLC separation was performed on a C18 column with ultra-pure water and acetonitrile as gradient elution at a flow rate of 0.4 mL/min at 30°C. Analyst TM Version 1.5.2 (Applied Biosystems) was used for data acquisition. The total chromatographic run time was 1.6 min. Results: LC/MS/MS method used for TDM of mezlocillin in children was developed and validated. This assay has a lower limit of quantification of 0.025 μg/mL for mezlocillin with 50 μL plasma. Good linearity was achieved for mezlocillin over the range from 0.025 to 20 μg /mL. The acceptance criteria were met in all cases. Among 36 patients aged between 0.16-1.63 years old, only one patient had detectable trough concentration higher than 1 μg/mL. Conclusion: LC-MS/MS method with 50 μL plasma developed in this study was successfully applied to TDM of mezlocillin in children. The high variability of trough concentration highlighted that TDM is important to optimize mezlocillin therapy in children.

To realize the application of xylan based film in food and drug packaging, the poor mechanical property and film-forming property of xylan based film must be overcome. Herein, a good oxygen barrier composite film with desired mechanical properties was prepared based on carboxymethly xylan (CMX), chitosan (CS), and graphene oxide (GO). The results of scanning electron microscope revealed the composite film had a dense and continuous structure, which will endow the composite film with excellent mechanical property. As expected, the composite film with the 0.5% mass fraction of GO exhibited best mechanical property, among which the tensile stress, tensile strain, and Young's modulus of the composite film reached 50.81 MPa, 47.61%, and 1.39 GPa, respectively. The oxygen barrier properties of the composite films significantly increased with the addition of graphene oxide due to the dense, stacked multilayer structure. In addition, these composite films exhibited good antibacterial properties. Therefore, these films show great promise in the field of food packaging and wound dressing due to their excellent mechanical, oxygen barrier and antibacterial properties.

Purpose: SHP2 inhibitors offer an appealing and novel approach to inhibit receptor tyrosine kinase (RTK) signaling, which is the oncogenic driver in many tumors or is frequently feedback activated in response to targeted therapies including RTK inhibitors and MAPK inhibitors. We seek to evaluate the efficacy and synergistic mechanisms of combinations with a novel SHP2 inhibitor, TNO155, to inform their clinical development. Experimental Design: The combinations of TNO155 with EGFR inhibitors (EGFRi), BRAFi, KRASG12Ci, CDK4/6i, and anti–programmed cell death-1 (PD-1) antibody were tested in appropriate cancer models in vitro and in vivo, and their effects on downstream signaling were examined. Results: In EGFR-mutant lung cancer models, combination benefit of TNO155 and the EGFRi nazartinib was observed, coincident with sustained ERK inhibition. In BRAFV600E colorectal cancer models, TNO155 synergized with BRAF plus MEK inhibitors by blocking ERK feedback activation by different RTKs. In KRASG12C cancer cells, TNO155 effectively blocked the feedback activation of wild-type KRAS or other RAS isoforms induced by KRASG12Ci and greatly enhanced efficacy. In addition, TNO155 and the CDK4/6 inhibitor ribociclib showed combination benefit in a large panel of lung and colorectal cancer patient–derived xenografts, including those with KRAS mutations. Finally, TNO155 effectively inhibited RAS activation by colony-stimulating factor 1 receptor, which is critical for the maturation of immunosuppressive tumor-associated macrophages, and showed combination activity with anti–PD-1 antibody. Conclusions: Our findings suggest TNO155 is an effective agent for blocking both tumor-promoting and immune-suppressive RTK signaling in RTK- and MAPK-driven cancers and their tumor microenvironment. Our data provide the rationale for evaluating these combinations clinically.

Rapid fabrication of organohydrogels at room temperature without external stimuli is a challenge. Inspired by plant catechol chemistry, a self-catalytic system established using sodium lignosulfonate and copper(II) ions (Ls–Cu2+) has been developed and applied to fabricate organohydrogels rapidly with fascinating multifunctional properties. The Ls–Cu2+ pair can induce ammonium persulfate (APS) to generate free radicals at room temperature, and subsequently initiate the free radical polymerization of hydroxyethyl acrylamide (HEAA) in water–glycerol binary phases in less than 30 s, without the removal of oxygen. The presence of the Ls–Cu2+ pair also endows the organohydrogel materials with fascinating UV-blocking (∼100%) and electrically conductive properties, and thereby they can be exploited as epidermal sensors. Owing to the presence of glycerol, the as-prepared organohydrogel exhibits intriguing anti-freezing (∼−50 °C) and anti-drying abilities (22–60 °C). This work taps the potential of dynamic plant catechol chemistry in the field of organohydrogel materials.

An amazing and stable carbonized octahedral frame material Cu-PC@OFM was synthesized and characterized through HRTEM, SEM, XRD, XPS, and Raman spectroscopy and nitrogen adsorption/desorption analysis. In particular, the carbon matrix carrier loaded with nano-copper not only maintains the original structure, but also the nano copper particles generated in situ significantly improve the catalytic performance and stability. It was disclosed that the copper-based catalyst material Cu-PC@OFM showed high catalytic activity in the borrowing hydrogen reaction and the synthesis of 1-benzyl-2-aryl-1H-benzo[d]imidazole derivatives with high yields in water. This copper catalytic system provided a much greener and efficient catalyst for the synthesis of functionalized amines and 1-benzyl-2-aryl-1H-benzo[d]imidazoles with good recovery performance in water, which was the first example for the Cu-PC@OFM material-catalyzed synthesis of 1-benzyl-2-aryl-1H-benzo[d]imidazoles. In addition, a plausible reaction mechanism was proposed through some condition control experiments, deuterium labeling experiments and separation of intermediates experiments.

In the process of solvothermal synthesis of one-dimensional (1D) Zn–Dy Schiff base coordination polymers, 25% of tetraoxolene anions (X2tetraox2−) underwent a one-electron reduction in situ reaction to form X2tetraox3˙− radical anions, which was confirmed by using the νCO vibration Raman spectra. Both the X2tetraox2− anion and the X2tetraox3˙− radical anion act as bridging ligands to connect two Zn–Dy Schiff base structural units, [DyZn(LSchiff)(NO3)(MeOH)]2+ (H2LSchiff = N,N′-bis(3-methoxysalicylidene)-1,3-diaminopropane) and [DyZn(LSchiff)(MeOH)2]3+, and finally assemble into two ionic zigzag chain-like coordination polymers, [Dy2Zn2(LSchiff)2(X2tetraox2−)1.5(X2tetraox3˙−)0.5(NO3)(MeOH)3](ClO4)0.5·2MeOH [1: X = Cl and 2: X = Br]. The two 1D Zn–Dy heterometallic coordination polymers exhibit the properties of single-molecule magnets (SMMs) and exhibit two-step magnetic relaxation behaviors under a dc field of 1500 Oe. Their effective energy barriers are adjusted by halogenated groups on the bridging ligands X2tetraox2− and X2tetraox3˙−.

Skin care biomaterials from natural compounds are increasingly needed in recent. We demonstrate a simple strategy to fabricate the dialdehyde xylan (DAX) crosslinked hydrogel with skin care potential. The hydrogel mainly consists of dialdehyde xylan, which is used as crosslinker for gelatin (G). Glycerol (Gly) and nicotinamide (NCA) are introduced here for improving the texture, antibacterial property as well as skin care functionality. The in vitro release results demonstrate that NCA can be released smoothly from the xylan-based gel, whereby the xylan-based fabricated gel can be utilized as an ideal matrix gel in skin care with loading and release function. The antibacterial ability is in the following order: Yeast > Bacillus subtilis > Staphylococcus aureus. The cytocompatibility experiments confirm the excellent viability of the gel. These merits demonstrate the fabricated hydrogel as a potential material in skin care.

Lithium-sulfur (Li-S) batteries have recently become a research hotspot because of their tempting theoretical capacity and energy density. Nevertheless, the notorious shuttle of polysulfides hinders the advancement of Li-S batteries. Herein, a two-dimensional covalent organic framework (COF) with extended π-conjugated units has been designed, synthesized, and used as sulfur recipients with 88.4 wt % in loading. The COF offers an elaborate platform for sufficient Li-S redox reactions with almost theoretical capacity release (1617 mA h g-1 at 0.1 C), satisfactory rate capability, and intensively traps polysulfides for a decent Coulombic efficiency (ca. 98.0%) and extremely low capacity decay (0.077% per cycle after 528 cycles at 0.5 C). The structural factors of the COF on the high-performance batteries are revealed by density functional theory calculations to be the high degrees of conjugation and proper interlayer space. This work not only demonstrates the great potential of COFs as highly efficient sulfur recipients but also provides a viable guidance for further design of COF materials to tackle shuttling issues toward active materials in electrochemical energy storage.

Improving the mechanical performance of hemicellulose-based hydrogel is an enormous challenge. Here, we propose a new strategy to achieve the hemicellulose-based hydrogels with superior mechanical performance through chain extension and semi-interpenetrating polymeric networks (semi-IPN). Xylan, known as the main type of hemicelluloses in angiosperms, is successfully modified to increase molecular weight by reductive amination reaction, overcoming the major limitation of brittleness. Then, the chemical network is obtained by graft copolymerizing acrylic acid (AA) with cross-linking agent N,N′-methylenebisacrylamide (MBA) in the presence of chain extended xylan (CEX). With the further introduction of ferric ions, a physical network is constructed via metal–ligand interactions. Such a xylan-based semi-IPN hydrogel shows excellent mechanical properties with a fracture tensile stress of 1.4 MPa, compression stress of 0.59 MPa, and the elongation at break of 1136%. In addition, the hydrogel also exhibits fine water absorbency (213.6 g/g) and high electrical conductivity (4.76 × 10–3 S/m). We anticipate that the resultant xylan-based semi-IPN hydrogels will open up a new approach for the design of high performance hemicellulose-based soft materials.

A heteropore covalent organic framework (COF) integrating tetraphenylethene skeleton and catechol segment is designed and synthesized. It exhibits extremely high stability in water under different pH conditions, which makes it an excellent material for adsorptive removal of Cd(II) from aqueous solutions with very fast adsorption kinetics, high uptake capacity, and good recyclability.

With the development of green chemistry, it is still a challenge to maintain the unstable valence state of the metal in heterogeneous catalysts and realize new catalytic synthesis methods. In this paper, it was reported that an univalent copper nanocomposite (Cu@Al/SBA-15) could efficiently catalyze the formation of novel amino-containing benzotriazoles with great fluorescence properties in a new synthetic strategy. Subsequently, its application was further verified by acylation reaction to produce a series of novel benzotriazoles derivatives with high yield. It was worth noting that Cu@Al/SBA-15 nanocomposites not only enable the reaction completed with high yield in a short time, but also could be recycled many times without a significant reduction in activity, and the leaching of copper and aluminum species in reaction system was negligible. Finally, the detailed and feasible reaction mechanism was also provided.

Non-Newtonian fluids are ubiquitous in daily life and industrial applications. Herein, we report an intelligent fluidic system integrating two distinct non-Newtonian rheological properties mediated by an autocatalytic enzyme reaction. Associative polyelectrolytes bearing a small amount of ionic and alkyl groups are engineered: by carefully balancing the charge density and the hydrophobic effect, the polymer solutions demonstrate a unique shear thickening property at low pH while shear thinning at high pH. The urea-urease clock reaction is utilized to program a feedback-induced pH change, leading to a strong upturn of the nonlinear viscoelastic properties. As long as the chemical fuel is supplied, two distinct non-Newtonian states can be achieved with a tunable lifetime span. As a proof of concept, we demonstrate how the physical energy-driven nonequilibrium properties can be manipulated by a chemical-fueled process.

SHP2 mediates RAS activation downstream of multiple receptor tyrosine kinases (RTKs) and cancer cell lines dependent on RTKs are in general dependent on SHP2. Profiling of the allosteric SHP2 inhibitor SHP099 across cancer cell lines harboring various RTK dependencies reveals that FGFR-dependent cells are often insensitive to SHP099 when compared to EGFR-dependent cells. We find that FGFR-driven cells depend on SHP2 but exhibit resistance to SHP2 inhibitors in vitro and in vivo. Treatment of such models with SHP2 inhibitors results in an initial decrease in phosphorylated ERK1/2 (p-ERK) levels, however p-ERK levels rapidly rebound within two hours. This p-ERK rebound is blocked by FGFR inhibitors or high doses of SHP2 inhibitors. Mechanistically, compared with EGFR-driven cells, FGFR-driven cells tend to express high levels of RTK negative regulators such as the SPRY family proteins, which are rapidly downregulated upon ERK inhibition. Moreover, over-expression of SPRY4 in FGFR-driven cells prevents MAPK pathway reactivation and sensitizes them to SHP2 inhibitors. We also identified two novel combination approaches to enhance the efficacy of SHP2 inhibitors, either with a distinct site 2 allosteric SHP2 inhibitor or with a RAS-SOS1 interaction inhibitor. Our findings suggest the rapid FGFR feedback activation following initial pathway inhibition by SHP2 inhibitors may promote the open conformation of SHP2 and lead to resistance to SHP2 inhibitors. These findings may assist to refine patient selection and predict resistance mechanisms in the clinical development of SHP2 inhibitors and to suggest strategies for discovering SHP2 inhibitors that are more effective against upstream feedback activation.

Three novel isostructural Zn2Ln2 cluster complexes with carbonate bridging ligands, {Zn2Ln2(μ3-CO3)2L2(acacF6)2}·CH3OH [H2L = N,N′-dimethyl-N,N′-(2-hydroxy-3-methoxy-5-methyl-benzyl)ethylenediamine; HacacF6 = hexafluoroacetylacetone; Ln = Dy, 1; Ln = Gd, 2; Ln = Eu, 3], have been prepared by fixing carbon dioxide in the atmosphere. Such carbonate bridging ligands may mediate ferromagnetic exchange between Ln3+ ions. The Zn2Dy2 compound (1) displays the properties of a single molecule magnet (SMM), showing slow magnetic relaxation at a 1500 Oe dc field, with an obviously larger Ueff/k value (83 K) with respect to the other carbonate-bridged Zn2Dy2 SMMs (≤34 K) and ZnDy dinuclear SMMs derived from the same ligand H2L used in this work (≤36.5 K), while the Zn2Gd2 compound (2) shows a moderate magnetocaloric effect and can be looked upon as a potential molecular material for low temperature magnetic refrigeration.

Oil-in-water food emulsions consisting of natural emulsifiers has been an active field of green scientific inquiry. Here, we extract two types of new hemicellulose-based emulsifiers (HH and HL) from holocellulose and dewaxed materials of bamboo (Phyllostachys pubescens), as well as compare their emulsifying soy oil ability, respectively. The main content of HH is arabinoxylan, while the primary composition in HL is glucan. The emulsifying capacity of these two types of hemicellulose-based emulsifiers are evaluated by droplet size distribution, surface charge and optical microscopy. Since HL possesses higher lignin and protein residual contents, the resultant emulsion exhibits smaller droplets and higher emulsion stability. In comparison, HH emulsifier has almost no emulsifying capacity due to the lack of non-polar groups. This study provides insight into the choice of hemicelluloses-based emulsifiers for the formation of stable oil-in-water food emulsions.

Constructing gas-sensitive hydrogels is a new direction of soft matter. Carbon monoxide (CO) is one of the most vital gas molecules in living organisms, whose dysfunction is related to serious human diseases. Here, we report a CO-responsive self-healing hydrogel system that is formed by a palladium (Pd)-cross-linked polymer network. The introduction of dynamic Pd-bridged metal-coordination units into the macromolecular chains can endow the network with CO-triggered gel-to-sol transition behavior and fast recoverable capacity to mechanical damage. We envisage that this polymer hydrogel would expand the repertoire of metal hydrogels and provide a new platform for gas-stimulated smart soft materials.

Under solvothermal conditions, five chiral 3d–4f wheel-like heterometallic hexanuclear clusters with the Schiff base ligand [H2L = N,N′-bis(3-methoxysalicylidene)-1,3-diaminopropane] were synthesized by the in situ ligand reaction of the 1,3-bis(2-pyridyl)-1,3-propanedione and generated the pyridine-2-carboxylate (PyCO2−) that acted as a bridging ligand; a peroxide anion formed by the spontaneous reduction of dioxygen plays a key role in the assembly of these complexes. The five isomeric 3d–4f heterometallic complexes, with molecular formula [M3Ln3(O2)L3(PyCO2)3](OH)2(ClO4)2·8H2O (M = Zn, Cu; Ln = Dy, Tb, Gd) represent the first anion-orientated chiral heterometallic cluster complexes composed of achiral components. Except for complex 1, we randomly measured the crystal structure of one of the two chiral enantiomers of complexes 2–5. Magnetic measurements show that the Zn3Gd3 complex exhibits a moderate magnetocaloric effect. The Cu3Tb3 complex is a single-molecule magnet (SMM) with an energy barrier (Ueff/k) value of 31.7(0.3) K under zero dc field, which is a larger value for Cu–Tb SMMs; the other three compounds Zn3Dy3, Zn3Tb3, and Cu3Dy3 exhibit field-induced magnetic relaxation. The Ueff/k value of Zn3Dy3 [>100 K, Hdc = 1000 Oe] is obviously larger than those of equilateral triangular Dy3 complexes (≤62 K).

Fluidic materials that exhibit an engineered non-Newtonian response are highly desirable in industrial and military applications. For example, shear thickening is highly intriguing in the case of flexible body armor or damping devices; however, shear thinning is more suitable in industrial processes with confining flow or painting. Herein we present a new class of non-Newtonian polymeric fluids with switchable rheological properties being mediated by carbon dioxide (CO2). Several pH-sensitive associative amphiphilic polymers were designed by copolymerizing N,N-dimethylacrylamide (DMA) and N,N-dimethylaminoethyl methacrylate (DMAEMA), followed by hydrophobic modification. In the beginning, polymers carrying an optimal balance of hydrophilic and hydrophobic moieties exhibit shear thinning properties in an alkaline environment. After CO2 aeration, the protonation of tertiary amine groups on the polymer backbone induces coil expansion and promotes interchain cross-linking under shear, leading to an abnormal shear thickening. The fluidic material can regain its shear thinning properties after sparging the solution with N2. Such a gas-controlled process is reversible and clean, which can be performed over multiple cycles. This study taps the potential of CO2 utilization in the dynamic fluidic materials science.

Based on iminopyridine ligands (L1–L3), Fe(II) (Fe1–Fe3) and Co(II) (Co1–Co3) complexes were synthesized and characterized well. According to single-crystal XRD studies, Co3 exhibits a dimeric structure with a four-coordinated metal center. Whereas, the iron complexes (Fe1 and Fe3) coordinate with two ligands to form a distorted-octahedral and distorted-trigonal bipyramidal geometry, respectively. All these catalysts were tested for the polymerization of isoprene. Using MAO as the co-catalyst, the Fe3 catalyst containing a bulky substituent can provide trans-1,4-unit (64%) polyisoprenes, while the Fe1 catalyst afforded trans-1,4-unit polyisoprenes (32%). Conversely, the combination of EASC as the co-catalyst with Fe1–Fe3 catalysts can give 1,4-unit polyisoprenes with high trans-1,4-unit selectivity (up to 88%). The central metal atom of the catalysts plays a crucial role in isoprene polymerization and significantly affects their activity. Fe(II) catalysts showed the highest activity (up to 99% yield), and afforded polyisoprenes with high molecular weights (191 kg mol−1). However, Co(II) systems exhibited lower activity (60% yield) and the obtained polyisoprenes were of lower molecular weights (2.15 kg mol−1) with broad molecular weight distribution.

KRAS, an oncogene mutated in nearly one third of human cancers, remains a pharmacologic challenge for direct inhibition except for recent advances in selective inhibitors targeting the G12C variant. Here, we report that selective inhibition of the protein tyrosine phosphatase, SHP2, can impair the proliferation of KRAS-mutant cancer cells in vitro and in vivo using cell line xenografts and primary human tumors. In vitro, sensitivity of KRAS-mutant cells toward the allosteric SHP2 inhibitor, SHP099, is not apparent when cells are grown on plastic in 2D monolayer, but is revealed when cells are grown as 3D multicellular spheroids. This antitumor activity is also observed in vivo in mouse models. Interrogation of the MAPK pathway in SHP099-treated KRAS-mutant cancer models demonstrated similar modulation of p-ERK and DUSP6 transcripts in 2D, 3D, and in vivo, suggesting a MAPK pathway–dependent mechanism and possible non-MAPK pathway–dependent mechanisms in tumor cells or tumor microenvironment for the in vivo efficacy. For the KRASG12C MIAPaCa-2 model, we demonstrate that the efficacy is cancer cell intrinsic as there is minimal antiangiogenic activity by SHP099, and the effects of SHP099 is recapitulated by genetic depletion of SHP2 in cancer cells. Furthermore, we demonstrate that SHP099 efficacy in KRAS-mutant models can be recapitulated with RTK inhibitors, suggesting RTK activity is responsible for the SHP2 activation. Taken together, these data reveal that many KRAS-mutant cancers depend on upstream signaling from RTK and SHP2, and provide a new therapeutic framework for treating KRAS-mutant cancers with SHP2 inhibitors.

One-pot template construction of α,α′-bis(arylimino)-2,3:5,6-bis(pentamethylene)pyridyl iron chlorides achieved by reacting α,α′-dioxo-2,3:5,6-bis(pentamethylene)pyridine and the corresponding anilines along with the respective iron chloride in acetic acid provided yields of 26–76%. All these complexes were characterized by FT-IR, elemental analysis, 1H NMR, and X-ray diffraction analysis. Distorted-square-pyramidal geometries are observed in the molecular structures of Fe1 and Fe6, respectively. When MAO or MMAO is used as a cocatalyst, Fe1–Fe5 display a high activity of 107 g with highly linear, low-molecular-weight, and narrow-polydispersity polyethylenes (PEs) being obtained by ethylene polymerization. The catalytic activity of Fe1 reached a maximum activity ((3.81–3.93) × 107 g of PE (mol of Fe)−1 h–1) by using the cocatalyst MAO or MMAO at Al/Fe ratio of 5000. All of the synthesized iron precatalysts Fe1–Fe8 containing sterically ortho benzhydryl and aryl (2,4,6-substituents of the aryl ring) groups...

As a base for neutralizing homochiral dicarboxylic acids [R-/S-2-methylglutaric acid, abbreviated as (R/S)-2-MG] rather than an N-donor ligand, 1,3-di(4-pyridyl)propane participates in the self-assembly of isostructural, homochiral lanthanide(III) coordination polymers derived from (R/S)-2-MG at room temperature, which show 2D sinusoidal ruffling (4, 4) network structures with the formulas {[Eu2(R-2-MG)3(H2O)4]·0.5H2O}n (Eu-R1), {[Gd2(R-2-MG)3(H2O)4]·0.5H2O}n (Gd-R2), {[Tb2(R-2-MG)3(H2O)4]·0.5H2O}n (Tb-R3), and {[Dy2(R-2-MG)3(H2O)4]·0.5H2O}n (Dy-R4) as well as {[Eu2(S-2-MG)3(H2O)4]·0.5H2O}n (Eu-S1), {[Gd2(S-2-MG)3(H2O)4]·0.5H2O}n (Gd-S2), {[Tb2(S-2-MG)3(H2O)4]·0.5H2O}n (Tb-S3), and {[Dy2(S-2-MG)3(H2O)4]·0.5H2O}n (Dy-S4). Among them, the europium(III) and terbium(III) compounds show solid fluorescent properties characteristic of lanthanide(III) ions, while the dysprosium(III) compound may exhibit magnetic relaxation. Furthermore, the magnetic entropy change or magnetocaloric effect of the gadolinium(III) c...

FGFR1 was recently shown to be activated as part of a compensatory response to prolonged treatment with the MEK inhibitor trametinib in several KRAS-mutant lung and pancreatic cancer cell lines. We hypothesize that other receptor tyrosine kinases (RTK) are also feedback-activated in this context. Herein, we profile a large panel of KRAS-mutant cancer cell lines for the contribution of RTKs to the feedback activation of phospho-MEK following MEK inhibition, using an SHP2 inhibitor (SHP099) that blocks RAS activation mediated by multiple RTKs. We find that RTK-driven feedback activation widely exists in KRAS-mutant cancer cells, to a less extent in those harboring the G13D variant, and involves several RTKs, including EGFR, FGFR, and MET. We further demonstrate that this pathway feedback activation is mediated through mutant KRAS, at least for the G12C, G12D, and G12V variants, and wild-type KRAS can also contribute significantly to the feedback activation. Finally, SHP099 and MEK inhibitors exhibit combination benefits inhibiting KRAS-mutant cancer cell proliferation in vitro and in vivo. These findings provide a rationale for exploration of combining SHP2 and MAPK pathway inhibitors for treating KRAS-mutant cancers in the clinic.

The ortho-benzhydryl-substituted α,α′-bis(arylimino)-2,3:5,6-bis(pentamethylene)pyridine-chromium(III) chlorides, [2,3:5,6-{C4H8C(N(2-R1-4-R2-6-(CHPh2)C6H2)}2C5HN]CrCl3 [R1 = R2 = Me Cr1, R1 = Me, R2 = CHPh2 Cr2, R1 = Et, R2 = CHPh2 Cr3, R1 = i-Pr, R2 = CHPh2 Cr4, R1 = Cl, R2 = CHPh2 Cr5, R1 = F, R2 = CHPh2 Cr6], differing in the electronic and/or steric properties of their aryl-R1 and -R2 groups, have been prepared by a one-pot template approach involving α,α′-dioxo-2,3:5,6-bis(pentamethylene)pyridine, the corresponding aniline and CrCl3(THF)3 in acetic acid. The molecular structure of six-coordinate Cr1 reveals the carbocyclic-fused N,N,N-ligand to adopt a mer configuration with the puckered sections of the two fused rings arranged mutually cis. On activation with MAO or MMAO, Cr1 - Cr6 displayed high activities (up to 1.83 × 106 g (PE) mol−1 (Cr) h−1) for the polymerization of ethylene with the MAO-promoted polymerizations in most cases more productive than with MMAO. In general, the chromium complexes appended with ortho-halide substituents (Cr6 (F)) and (Cr5 (Cl)), proved the most active with the overall order being: Cr6 > Cr5 > Cr1 > Cr2 > Cr3 > Cr4. All catalysts formed linear polyethylene displaying a wide range of molecular weights (from 2.17 to 300.4 kg mol−1) that were highly dependent on the nature of the ortho-R1 substituent with fluoride Cr6 forming the lowest molecular weight and the most sterically demanding Cr4 (i-Pr) the highest.

Orchestrating conflicting polymerization mechanisms in a single polymerization process through one external stimulus is a prerequisite to achieve in-situ selective synthesis of different monomers. Here we report an electrochemically controlled mechanism transformation that enables selective activation of living cationic or radical polymerization via an alternating voltage and dual electrocatalysts. Using identical mixed-monomer condition, a variety of desired block copolymer structures, including diblock, multiblock, random, and tapered copolymers can be obtained by simply varying the periods or phases of the alternating potential. Moreover, merging this electro-interconverted polymerization with a flow-chemistry technique can streamline preparation of functional polymer materials with complex multiblock structure. This study would offer a new vision on large-scale electrochemical synthesis of sequence-defined polymers.

Dichroic circular polarizers (DCP) represent an important group of optical filters that transfer only that part of the incident light with the desired polarization state and absorb the remainder. However, DCPs are usually bulky and exhibit significant optical loss. Moreover, the integration of these kinds of DCP devices can be difficult and costly as different compositions of chemicals are needed to achieve the desired polarization status. Circular polarizers based on metasurfaces require only thin films in the order of hundreds of nanometers but are limited by their sensitivity to angle of incidence. Furthermore, few existing solutions offer broadband operation in the visible range. By using computational simulations, this paper proposes and analyses a plasmonic DCP structure operating in the visible, from 400 nm to 700 nm which overcomes these drawbacks. The resulting circular dichroism transmission (CDT) is more than 0.9, and the maximum transmission efficiency is greater than 78% at visible wavelengths. These CDT characteristics are largely independent of angle of incidence up to angles of 80 degrees.

SHP2 is a nonreceptor protein tyrosine phosphatase encoded by the PTPN11 gene 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 vivo antitumor 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.

Drug elimination alteration has been well reported in acute lymphoblastic leukemia (ALL). Considering that transporters and glomerular filtration influence, to different extents, the drug disposition, and possible side effects, we evaluated the effects of ALL on major renal transporters and glomerular filtration mediated pharmacokinetic changes, as well as expression of renal drug transporters. ALL xenograft models were established and intravenously injected with substrates of renal transporters and glomerular filtration separately in NOD/SCID mice. The plasma concentrations of substrates, after single doses, were determined using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). With the development of ALL, protein expression of MDR1, OAT3 and OCT2 were increased by 2.62-fold, 1.70-fold, and 1.45-fold, respectively, whereas expression of MRP2 and MRP4 were significantly decreased by 30.98% and 45.28% in the kidney of ALL groups compared with control groups. Clearance of MDR1-mediated digoxin, OAT3-mediated furosemide, and OCT2-mediated metformin increased by 3.04-fold, 1.47-fold, and 1.26-fold, respectively. However, clearance of MRPs-mediated methotrexate was reduced by 39.5%. These results are consistent with mRNA expression. Clearance of vancomycin and amikacin, as markers of glomerular filtration rate, had a 2.14 and 1.64-fold increase in ALL mice, respectively. The specific alteration of renal transporters and glomerular filtration in kidneys provide a rational explanation for changes in pharmacokinetics for ALL.

Six types of 2,8-bis(imino)-7,7-dimethyl-5,6-dihydroquinoline, 2-(ArN[double bond, length as m-dash]CMe)-8-(ArN)-7,7-Me2C9H6N (Ar = 2,6-Me2C6H3L1, 2,6-Et2C6H3L2, 2,6-iPr2C6H3L3, 2,4,6-Me3C6H2L4, 2,6-Et2-4-MeC6H2L5, 2,4,6-tBu3C6H3L6), distinguishable by their steric and electronic profile, are described that can readily undergo complexation with cobaltous chloride to form their corresponding LCoCl2 chelates, Co1-Co6. The molecular structures of Co2 and Co3 reveal square pyramidal geometries with ring puckering a feature of the gem-dimethyl section of their unsymmetrical N,N,N'-ligands. On activation with either methylaluminoxane (MAO) or modified methylaluminoxane (MMAO), all the cobalt complexes exhibited exceptionally high activities for ethylene polymerization with levels reaching up to 1.19 × 107 g PE per mol (Co) per h for mesityl-containing Co4. Significantly, these catalysts exhibited good thermal stability by displaying their optimal performance at temperatures up to 70 °C whilst also maintaining appreciable catalytic lifetimes. With the exception of that obtained using the most sterically hindered Co6 (2,4,6-t-butyl), the polyethylenes are of low molecular weight (Mw≤16.0 kg mol-1) and of narrow dispersity (Mw/Mn≤3.4). Moreover, end-group analysis of these highly linear polymer waxes reveals evidence for unsaturated as well as various levels of fully saturated materials highlighting the role of both β-H elimination and chain transfer to aluminum as termination pathways.

Herein, a series of dialkylaluminum 2-substituted 6,6-dimethylcyclopentyl pyridin-7-oxylates Al1-Al7 were synthesized and characterized by 1H- and 13C-NMR spectroscopy and elemental analysis. The molecular structure of Al3 was proven to be a dimer of an aluminum complex. These aluminum complexes could efficiently initiate the ring-opening polymerization (ROP) of e-caprolactone (CL), and the structural differentiations of the resultant PCL were strongly dependent on the amount of BnOH (PhCH2OH) used. In the absence of BnOH, the resultant PCL showed a cyclic structure, whereas BnO-capped linear PCL was obtained in the presence of >2.0 equivalents of BnOH; the resultant PCL was a mixture of linear and cyclic PCLs in the presence of 1.0 equivalent of BnOH. Moreover, these aluminum complexes exhibited high efficiency towards the ROP of l-lactide (LLA); however, the activities were lower than those for the ROP of e-CL. Without BnOH, the resultant PLLA showed a highly linear structure with the alkyl-end group from aluminum complexes; on the other hand, PLLA displayed a major cyclic structure and minor BnO-capped linear PLLA if 1.0 equivalent of BnOH was employed, and the percentage of BnO-capped linear PLLA was increased by increasing the amount of BnOH.

The design of structurally dynamic molecular networks can offer strategies for fabricating stimuli-responsive adaptive materials. Herein we first report a gas-responsive dynamic gel system based on frustrated Lewis pair (FLP) chemistry. Two trefoil-like molecules with bulky triphenylborane and triphenylphosphine groups are synthesized as complementary Lewis acid and base with trivalent sites. They can together bind CO2 gas molecules and further form a cross-linked network via the bonding interactions between FLPs and CO2 . Such CO2 -bridged dative linkages are shown to be dynamic covalent bonds, which endow the frustrated Lewis network with adaptable behaviors and unprecedented gas-regulated viscoelastic, mechanical, and self-healing performance. This study is an initial attempt to apply the FLP concept in materials chemistry, but we believe that this strategy will open a promising future for gas-sensitive smart materials.

Electronically and sterically enhanced Fe (II) chloride complexes (Fe1 Fe6) bearing 2-(1-(2,6-dibenzhydryl-4-nitrophenylimino)ethyl)-6-(1-(arylimino)ethyl)pyridine (aryl = 2,6-Me2Ph L1, 2,6-Et2Ph L2, 2,6-iPr2Ph L3, 2,4,6-Me3Ph L4 and 2,6-Et2-4-MePh L5) and 2,6-bis(1-(2,6-dibenzhydryl-4-nitrophenylimino)ethyl)pyridine (L6) ligands have been prepared. In addition to the elemental and spectroscopic analysis of all new compounds; the molecular structures of Fe1, Fe2 and Fe6 have been subject of the X-ray diffraction. The catalytic potential of all the complexes was investigated for ethylene polymerization and compared with the results of prototypal precatalyst, 2,6-bis(1-(2,6-diisopropylphenylimino)ethyl)pyridyliron chloride (Fe0). On treatment with MAO and MMAO co-catalysts, Fe6 was essentially inactive, while the iron complexes (Fe1 Fe5) displayed exceptionally high activities as high as 2.53 × 107 gPE (mol of Fe)−1 h−1 at 50 °C and 3.86 × 106 gPE (mol of Fe)−1 h−1 at 100 °C, and afforded high molecular weight polyethylene up to 610.6 kg/mol. By comparing with catalytic performance of the reported bis(imino)pyridine-iron precatalysts bearing non-nitro para-substituents (CH3, Cl) including Fe0, these values of activity and molecular weight are found to be the highest reported up to date. Additionally, the resultant polyethylenes are characteristically linear as being confirmed by DSC (Tm = 125.3–135.6 °C) and high-temperature 13C NMR measurments.

A family of six CH(phenol)-bridged bimetallic bis(imino)pyridine-iron(II) chlorides, CH(C6H4-4-OH){2′-(4-C6H2-2,6-(R1)2N═CMe)-6′-(2″,6″-(R2)2-4-(R3)C6H2N═CMe)C5H3N}2Fe2Cl4 [R1 = R2 = Me, R3 = H, Fe1; R1 = R2 = Et, R3 = H, Fe2; R1 = Me, R2 = Et, R3 = H, Fe3; R1 = Me, R2 = i-Pr, R3 = H, Fe4; R1 = R2 = R3 = Me, Fe5; R1 = R2 = Et, R3 = Me, Fe6], has been synthesized by the reaction of the corresponding compartmental ligand with 2 equiv of FeCl2·4H2O. The molecular structure of Fe6 reveals an intramolecular Fe···Fe separation of 10.152 A, with pairs of Fe6 assembling through intermolecular OH···Cl hydrogen bonding interactions. On activation with MAO or MMAO, Fe1–Fe6 exhibited both good thermal stability and very high activity for ethylene polymerization with the least sterically bulky compound, Fe1, being the standout performer (up to 2.43 × 107 g·mol–1(Fe)·h–1 at 60 °C). Notably, Fe1/MAO showed almost double the activity of a structurally related mononuclear catalyst while the resultant polyethylene exhibite...

The 8-(arylimino)-5,6,7-trihydroquinoline-nickel(II) chlorides, [8-N{2,6-R2-4-(C15H13)C6H2}C9H8N]NiCl2 (R = Me Ni1, Et Ni2, i-Pr Ni3, F Ni4, Cl Ni5), each appended with a remote para-dibenzocycloheptyl group, have been synthesized from either the pre-formed ligand (Ni1–Ni3) or by generating the ligand in-situ during complexation (Ni4, Ni5). The molecular structures of Ni2 and Ni3 adopt dimeric or trimeric forms in the solid state, in which the chlorides can act as doubly or triply bridging ligands. On treatment with either MMAO or Et2AlCl, Ni1–Ni5 showed low (Ni4, Ni5) to high activities (Ni1–Ni3: up to 4.58 × 106 g PE mol−1 (Ni) h−1) for ethylene polymerization producing unsaturated polyethylenes of low molecular weight (1.4–2.7 kg·mol−1) and narrow dispersity ( CH CH ) with respect to terminal vinyls ( CH CH2). The ortho-substituents of the precatalyst were found to not only affect the catalytic activity but also the vinylene:vinyl ratio and the branching content. Notably, the materials generated using ortho-fluoro Ni4/Et2AlCl possessed the least number of branches and an increased vinyl contribution. Furthermore, these unsaturated polyethylenes can be readily functionalized by epoxidation with almost quantitative conversion.

Two novel 3D pure inorganic compounds based on [Cr2Dy4(μ4-O)2(μ3-OH)4]10+ cluster units and sulfate anions are presented. Both complexes exhibit single-molecule-magnet (SMM)-like behavior. Permutation of the magnetic moment direction among SMM-like cluster units has a significant effect on the performance of molecular nanomagnets, and directional consistency shows obvious advantages.

Juglans mandshurica is a fast growing hard species, which is a tree in family of Juglandaceae and has a wide distribution in China, Korea and eastern Russia. Plant materials from J. mandshurica have extensively been used in folk medicines to prevent or cure gastric, esophageal, lung and cardiac cancer. As one chain of our searching for anticomplementary agents from natural sources, two epimeric ellagitannins, [2,3-O-4,4′,5,5′,6,6′,-hexahydroxydiphenoyl (HHDP))-(α,β)-D-glucose] (I) and pedunculagin (II) were purified from 70% acetone extracts of the stem barks of J. mandshurica by Thin Layer Chromatography and Sephadex LH-20 column chromatography approaches. The chemical structures of the isolated compounds were characterized by MS, NMR, and a careful comparation with published literatures. The epimeric ellagitannins I and II exhibited inhibitory properties against a classical pathway of complementary system with 50 % inhibitory concentrations (IC50) values of 65.3 and 47.7 μM, respectively, comparing with riliroside (IC50=104 μM) and rosmarinic acid (IC50=182 μM), which were used as positive controls. Thus, the work indicated both the two secondary metabolites possess excellent inhibitory activity and might be developed as potential anticomplementary chemicals.