Iodine-Promoted Reductive Sulfenylation Using Ketones as Hydride Donors.

Herein, an iodine-promoted reductive sulfenylation reaction of ketones with disulfides has been developed. This method provides an approach for synthesizing unsymmetrical alkyl-alkyl and alkyl-aryl sulfides in a single step. Investigation of the reaction mechanism revealed that ketones play a dual role in this process. They react with disulfides to produce vinyl thioethers and act as effective organic hydride donors, reducing the number of vinyl thioethers that are formed in situ. This study expands the range of applications of ketones in chemical synthesis.

A Small-Molecule Inhibitor of Factor Inhibiting HIF Binding to a Tyrosine-flip Pocket for the Treatment of Obesity.

In animals limiting oxygen upregulates hypoxia-inducible factor (HIF) promoting a metabolic shift towards glycolysis. Factor inhibiting HIF (FIH) is an asparaginyl hydroxylase that regulates HIF function by reducing its interaction with histone acetyl transferases. HIF levels are negatively regulated by the HIF prolyl hydroxylases (PHDs), which like FIH, are 2-oxoglutarate(2OG) oxygenases. Genetic loss of FIH promotes both glycolysis and aerobic metabolism. FIH has multiple non-HIF substrates making it challenging to connect its biochemistry with physiology. A structure-mechanism guided approach identified a highly potent in vivo active FIH inhibitor, ZG-2291, binding of which promotes a conformational flip of a catalytically important tyrosine, enabling selective inhibition of FIH over other JmjC subfamily 2OG oxygenases. Consistent with genetic studies, ZG-2291 promotes thermogenesis and ameliorates symptoms of obesity and metabolic dysfunction in ob/ob mice. The results reveal ZG-2291 as a useful probe for the physiological functions of FIH and identify FIH inhibition as a promising strategy for obesity treatment.

Novel NQO1 substrates bearing two nitrogen redox centers: Design, synthesis, molecular dynamics simulations, and antitumor evaluation.

By analyzing the crystal structure of NQO1, an additional binding region for the ligand was discovered. In this study, a series of derivatives with a novel skeleton bearing two nitrogen redox centers were designed by introducing amines or hydrazines to fit with the novel binding region of NQO1. Compound 24 with a (4-fluorophenyl)hydrazine substituent was identified as the most efficient substrate for NQO1 with the reduction rate and catalytic efficiency of 1972 ± 82 µmol NADPH/min/µmol NQO1 and 6.4 ± 0.4 × 106 M-1s-1, respectively. Molecular dynamics (MD) simulation revealed that the distances between the nitrogen atom of the redox centers and the key Tyr128 and Tyr126 residues were 3.5 Å (N1-Tyr128) and 3.4 Å (N2-Tyr126), respectively. Compound 24 (IC50/A549 = 0.69 ± 0.09 µM) showed potent antitumor activity against A549 cells both in vitro and in vivo through ROS generation via NQO1-mediated redox cycling, leading to a promising NQO1-targeting antitumor candidate.

A Carbon-Carbon Bond Cleavage-Based Prodrug Activation Strategy Applied to ß-Lapachone for Cancer-Specific Targeting.

Prodrugs are one of the most common strategies for the design of targeted anticancer agents. However, their application is often hampered by the modifiable groups available on parent drugs. Herein, a carbon-carbon (C-C) bond cleavage-based prodrug activation strategy is reported, which was successfully used to design prodrugs of ß-lapachone (ß-lap), an ortho-quinone natural product without traditional modifiable groups for the construction of C-N/C-O bond cleavage-based prodrugs. The designed ß-lap prodrug with a reactive oxygen species-specific trigger was quickly activated, releasing ß-lap. It exerted anticancer efficacy via NAD(P)H:quinone oxidoreductase 1 (NQO1)-mediated futile redox cycling, resulting in potent cytotoxicity that was highly selective for NQO1-rich cancer cells over normal cells both in vitro and in vivo. This significantly amplified the therapeutic window of ß-lap. This study provides a practical strategy for the design of prodrugs for parent drugs that do not contain traditional modifiable groups.

In Situ Inhibitor Synthesis and Screening by Fluorescence Polarization: An Efficient Approach for Accelerating Drug Discovery.

Target-directed dynamic combinatorial chemistry has emerged as a useful tool for hit identification, but has not been widely used, in part due to challenges associated with analyses involving complex mixtures. We describe an operationally simple alternative: in situ inhibitor synthesis and screening (ISISS), which links high-throughput bioorthogonal synthesis with screening for target binding by fluorescence. We exemplify the ISISS method by showing how coupling screening for target binding by fluorescence polarization with the reaction of acyl-hydrazides and aldehydes led to the efficient discovery of a potent and novel acylhydrazone-based inhibitor of human prolyl hydroxylase 2 (PHD2), a target for anemia treatment, with equivalent in vivo potency to an approved medicine.

Iodine-Catalyzed Aerobic Oxidation of Spirovinylcyclopropyl Oxindoles to Form Spiro-1,2-dioxolanes Diastereoselectively.

A novel method of iodine-catalyzed aerobic oxidation with spirovinylcyclopropyl oxindoles under mild conditions has been described. A series of spiro-1,2-dioxolanes were prepared in good to excellent yields and considerable diastereoselectivities. The new approach is operationally simple, scalable, and tolerant of various functional groups.

Au-Catalyzed tandem intermolecular hydroalkoxylation/Claisen rearrangement between allylic alcohols and chloroalkynes.

An efficient protocol for the synthesis of γ,δ-unsaturated α-chloroketones has been developed via Au-catalyzed tandem intermolecular hydroalkoxylation/Claisen rearrangement. In the presence of 1 mol% JohnPhosAuCl and 1 mol% NaBArF, a broad range of allylic alcohols smoothly underwent the tandem intermolecular hydroalkoxylation/Claisen rearrangement with aromatic, vinylic or aliphatic chloroalkynes to give structurally diverse γ,δ-unsaturated α-chloroketones in excellent yields. Importantly, high Z/E selectivity was achieved. Other advantages are widespread availability of the substrates, compatibility with a broad range of functional groups and mild reaction conditions.

Synthesis of functionalized 2,5-dihydropyrrole derivatives via a convenient [3 + 2] annulation of azomethine ylides with allenoates.

A convenient [3 + 2] annulation of azomethine ylides with allenoates promoted by triethylamine produced highly functionalized 2,5-dihydropyrrole derivatives in moderate to excellent yields under mild conditions. The potential utility of this reaction indicates that this reaction could be performed on the gram scale and the synthesized functionalized 2,5-dihydropyrrole derivatives could be further transformed into other interesting heterocycles. The mechanism for the transformation is a tandem ß-addition/Mannich cyclization process.

Hydroxy-Assisted Regio- and Stereoselective Synthesis of Functionalized 4-Methylenepyrrolidine Derivatives via Phosphine-Catalyzed [3 + 2] Cycloaddition of Allenoates with o-Hydroxyaryl Azomethine Ylides.

In this work, we present a new strategy for the chemo-, regio-, and stereoselective synthesis of functionalized pyrrolidine derivatives via a hydroxy-assisted phosphine-catalyzed reaction of allenoates or substituted allenoates with o-hydroxyaryl azomethine ylides that offers a wide variety of 4-methylenepyrrolidine derivatives in synthetically useful yields with high stereoselctivities under mild conditions. Remarkably, it is the first example of highly regio- and stereoselective phosphine-catalyzed [3 + 2] cycloaddition of allenoates with o-hydroxyaryl azomethine ylides.

Palladium-catalyzed direct arylation of indoles with arylsulfonyl hydrazides.

A novel method to synthesise 2-arylindoles is demonstrated via direct arylation of indoles with arylsulfonyl hydrazides. Under the optimized reaction conditions, the reaction well tolerates a wide variety of functional groups to afford structurally diverse 2-arylindoles in good to excellent yields at 70 °C.

Prediction of Residual Life of In-Service P91 Steel Joints Based on Fracture Behavior.

P91 steel and P91 steel joints experience performance degradation after serving for 30,000 h in working conditions. To clarify the damage and failure behavior and remaining life of the joints during subsequent service, further creep testing was conducted on the welded joints of P91 steel that had been in service for 30,000 h at three temperatures: 550 °C, 575 °C, and 600 °C. The fracture surface and the cross-section damage behavior were characterized by SEM and EBSD methods. The results show that there are two types of fracture modes in the joints at different temperatures: ductile cracking occurring at the BM, and type IV cracking occurring in the FGHAZ. The threshold stress for fracture mode transition decreases with an increase in working temperature. Type IV cracking near the HAZ is the main reason for the premature failure of joints during service. And based on the fracture mode, the dual-constant L-M method was proposed to predict the strength of in-service joint materials. The testing data are discussed and classified based on the fracture mode in this method, which has high accuracy and can prevent the premature failure of joints.

Iodine-promoted transfer of dihydrogen from ketones to alkenes, triphenylmethyl, and diphenylmethyl derivatives.

Herein, a novel class of transfer hydrogenation agent, cycloheptanone, was successfully employed in metal-free hydrogenation facilitated by iodine. A series of alkenes, triphenylmethyl derivatives, and diphenylmethyl derivatives were reduced to the desired compounds in moderate to excellent yields. The transfer hydrodeuteration of alkenes using α-deuterated cyclododecanone exhibited high regioselectivity. Preliminary mechanism studies confirmed the origins of the two hydrogen atoms involved in the reduction of alkenes. The current study paves the way for the use of ketones as unique transfer hydrogenation agents in chemical synthesis.

Preferred Conformation-Guided Discovery of Potent and Orally Active HIF Prolyl Hydroxylase 2 Inhibitors for the Treatment of Anemia.

In this work, we discovered a novel series of prolyl hydroxylase 2 (PHD2) inhibitors with improved metabolic properties based on a preferred conformation-guided drug design strategy. Piperidinyl-containing linkers with preferred metabolic stability were designed to match the dihedral angle of the desired docking conformation in the PHD2 binding site with the lowest energy conformation. Based on the piperidinyl-containing linkers, a series of PHD2 inhibitors with high PHD2 affinity and favorable druggability were obtained. Remarkably, compound 22, with an IC50 of 22.53 nM toward PHD2, significantly stabilized hypoxia-inducible factor α (HIF-α) and upregulated the expression of erythropoietin (EPO). Furthermore, oral administration of 22 dose-dependently stimulated erythropoiesis in vivo. Preliminary preclinical studies showed that 22 has good pharmacokinetic properties and an excellent safety profile, even at 10 times the efficacious dose (200 mg/kg). Taken together, these results indicate that 22 is a promising candidate for anemia treatment.

In Situ Inhibitor Synthesis and Screening by Fluorescence Polarization: An Efficient Approach for Accelerating Drug Discovery.

Target-directed dynamic combinatorial chemistry has emerged as a useful tool for hit identification, but has not been widely used, in part due to challenges associated with analyses involving complex mixtures. We describe an operationally simple alternative: in situ inhibitor synthesis and screening (ISISS), which links high-throughput bioorthogonal synthesis with screening for target binding by fluorescence. We exemplify the ISISS method by showing how coupling screening for target binding by fluorescence polarization with the reaction of acyl-hydrazides and aldehydes led to the efficient discovery of a potent and novel acylhydrazone-based inhibitor of human prolyl hydroxylase 2 (PHD2), a target for anemia treatment, with equivalent in vivo potency to an approved medicine.

Rational designed highly sensitive NQO1-activated near-infrared fluorescent probe combined with NQO1 substrates in vivo: An innovative strategy for NQO1-overexpressing cancer theranostics.

Since NQO1 is overexpressed in many cancer cells, it can be used as a biomarker for cancer diagnosis and targeted therapy. NQO1 substrates show potent anticancer activity through the redox cycle mediated by NQO1, while the NQO1 probes can monitor NQO1 levels in cancers. High sensitivity of probes is needed for diagnostic imaging in clinic. In this study, based on the analysis of NQO1 catalytic pocket, the naphthoquinone trigger group 13 rationally designed by expanding the aromatic plane of the benzoquinone trigger group 10 shows significantly increased sensitivity to NQO1. The sensitivity of the naphthoquinone trigger group-based probe A was eight times higher than that of benzoquinone trigger group-based probe B in vivo. Probe A was selectively and efficiently sensitive to NQO1 with good safety profile and plasma stability, enabling its combination with NQO1 substrates in vivo for NQO1-overexpressing cancer theranostics for the first time.

Anisotropic Low Cycle Behavior of the Extruded 7075 Al Alloy.

The quasi-static and low cycle fatigue tests of extruded 7075 Al alloy (Φ200 mm) were investigated in three directions: the extrusion direction (ED), the radial direction (RD), and 45° with ED (45°). Grain morphology analysis, texture measurement, and fatigue fracture characterization were conducted to discuss the relationship between microstructure and mechanical properties. The experimental results showed that the ED specimen had higher ultimate tensile strength (UTS) and low cycle fatigue (LCF) properties, which were mainly attributed to the following three causes. First, the grain boundaries (GBs) had an obvious effect on the crack growth. The number of GBs in the three directions was different due to the shape of the grains elongated along the ED. Second, the sharp <111> texture and the small Schmidt factor along the ED explained the higher ultimate tensile strength (UTS) of the ED specimens. Third, fatigue fracture observation showed that the ED specimen had a narrow fatigue striation spacing, which indicated that the plastic deformation of the ED specimen was the smallest in each cycle. In addition, two fatigue prediction models were established to predict the LCF life of extruded 7075 Al alloy, based on the life response behavior of the three directions under different strains.

Discovery of a Potent and Orally Bioavailable Hypoxia-Inducible Factor 2α (HIF-2α) Agonist and Its Synergistic Therapy with Prolyl Hydroxylase Inhibitors for the Treatment of Renal Anemia.

Activation of hypoxia-inducible factor 2 (HIF-2) has emerged as a potent renal anemia treatment strategy. Here, the benzisothiazole derivative 26 was discovered as a novel HIF-2α agonist, which first demonstrated nanomolar activity (EC50 = 490 nM, Emax = 349.2%) in the luciferase reporter gene assay. Molecular dynamics simulations indicated that 26 could allosterically enhance HIF-2 dimerization. Furthermore, compound 26 had a good pharmacokinetic profile (the oral bioavailability in rats was 41.38%) and an in vivo safety profile (the LD50 in mice was greater than 708 mg·kg-1). In the in vivo efficacy assays, the combination of 26 and the prolyl hydroxylase inhibitor, AKB-6548, was confirmed for the first time to synergistically increase the plasma erythropoietin level in mice (from 260 to 2296 pg·mL-1) and alleviate zebrafish anemia induced by doxorubicin. These results provide new insights for HIF-2α agonists and the treatment of renal anemia.

Application of cation-π interactions in enzyme-substrate binding: Design, synthesis, biological evaluation, and molecular dynamics insights of novel hydrophilic substrates for NQO1.

Cation-π interaction is a type of noncovalent interaction formed between the π-electron system and the positively charged ion or moieties. In this study, we designed a series of novel NQO1 substrates by introducing aliphatic nitrogen-containing side chains to fit with the L-shaped pocket of NQO1 by the formation of cation-π interactions. Molecular dynamics (MD) simulation indicated that the basic N atom in the side chain of NQO1 substrates, which is prone to be protonated under physiological conditions, can form cation-π interactions with the Phe232 and Phe236 residues of the NQO1 enzyme. Compound 4 with a methylpiperazinyl substituent was identified as the most efficient substrate for NQO1 with the reduction rate and catalytic efficiency of 1263 ± 61 µmol NADPH/min/µmol NQO1 and 2.8 ± 0.3 × 106 M-1s-1, respectively. Notably, compound 4 exhibited increased water solubility (110 µg/mL) compared to that of ß-lap (43 µg/mL), especially under acidic condition (pH = 3, solubility > 1000 µg/mL). Compound 4 (IC50/A549 = 2.4 ± 0.6 µM) showed potent antitumor activity against NQO1-rich cancer cells through ROS generation via NQO1-mediated redox cycling. These results emphasized that the application of cation-π interactions by introducing basic aliphatic amine moiety is beneficial for both the water solubility and the NQO1-substrate binding, leading to promising NQO1-targeting antitumor candidates with improved druglike properties.

An Investigation on the Microstructure and Texture of an AZ80 Cup-Shaped Piece Processed by Rotating Backward Extrusion.

The rotating backward extrusion (RBE) process, as a new severe plastic deformation (SPD) process, is based on conventional backward extrusion and rotation, which meets the requirement of modern industrial development with its high performance and production efficiency. However, there is little research on the microstructure evolution and texture modification of the RBE process. Thus, in this study, the effect of different rotating revolutions, e.g., n = 5, n = 10, and n = 50, on the microstructure and texture development for the RBE process based on the AZ80 magnesium (Mg) alloy were investigated at 653 K. The results disclose that the rotating revolution is an influencing processing parameter on the deformation of the RBE process. The grain refining ability is enhanced with the increase of the rotating revolutions, and the minimum grain size of the cup bottom, shearing zone, and cup wall can reach to 16.7 µm, 15.6 µm, and 13.0 µm, respectively, under the condition of n = 50. Furthermore, with the increase in the rotating revolutions, the microstructure of the alloy becomes more uniform and the proportion of dynamic recrystallization (DRX) is also increased. The maximum DRX fractions of the sample for the cup bottom and cup wall are 95.4% and 86.8%, respectively, at n = 50. The DRX mechanism of the RBE process is determined by the continuous DRX and discontinuous DRX. In addition, the texture can be significant weakened during the RBE process, especially at the cup bottom, where the maximum pole intensity can be reduced from 17.6 at n = 10 to 6.5 at n = 50, which can be attributed to the higher proportion of new DRXed grains whose orientations are more random compared with the deformed grains.

Synthesis and biological activities of two camptothecin derivatives against Spodoptera exigua.

Camptothecin (CPT), a natural alkaloid isolated from Camptotheca acuminata Decne, is found to show potential insecticidal activities with unique action mechanisms by targeting at DNA-topoisomease I (Top1) complex and inducing cell apoptosis. To improve the efficacy against insect pests, two camptothecin (CPT) derivatives were synthesized through introducing two functional groups, 2-nitroaminoimidazoline and 1-chloro-2-isocyanatoethane by esterification reaction. The insecticidal activities of these two derivatives were evaluated at contact toxicity, cytotoxicity and topoisomerase I (Top1) inhibitory activities comparing with CPT and hydroxyl-camptothecin (HCPT). Results showed that compound a, synthesized by introducing 2-nitroaminoimidazoline to CPT, apparently increased contact toxicity to the third larvae of beet armyworm, Spodoptera exigua, and cytotoxicity to IOZCAS-Spex-II cells isolated from S. exigua. However, the inhibition on DNA relaxation activity of Top1 was reduced to less than 5 percentage even at high concentrations (50 and 100 µM). For introducing 1-chloro-2-isocyanatoethane to HCPT, the contact toxicity, cytotoxicity and Top1 inhibitory activity of synthesized compound b were increased significantly compared to CPT and HCPT. These results suggested that both synthesized compounds possessed high efficacy against S. exigua by targeting at Top1 (compound b) or novel mechanism of action (compound a).