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The formation of C–S bonds using cheap, stable and odorless sulfonyl chlorides and widely sourced and less toxic alcohols with the assistance of ADDP is reported.

A series of indole fused scaffolds was synthesized via cyclization reaction of 2-indolylmethanol with azonaphthalene. These reactions were realized under mild reaction conditions via catalyst control, providing structurally diverse indole derivative.

The development of enantioselective desymmetrization of para-quinamines with isocyanates catalyzed by chiral phosphoric acid is reported. The strategy provides concise access to functionalized imidazolidin-2-one derivatives in high yields and enantioselectivities under mild reaction conditions. Remarkably, this reaction could be performed on a gram scale using 5 mol % catalyst loading and the chiral imidazolidin-2-one derivatives could be easily transformed into valuable scaffolds without disturbing the enantiopurity, demonstrating the synthetic utility of this protocol.

Proprotein convertase subtilisin kexin 9 (PCSK9) has been identified as a reliable therapeutic target for hypercholesterolemia and coronary artery heart diseases since the monoclonal antibodies of PCSK9 have launched. Disrupting the protein-protein interaction (PPI) between PCSK9 and the low-density lipoprotein receptor (LDLR) has been considered as a promising approach for developing PCSK9 inhibitors. However, PPIs have been traditionally considered difficult to target by small molecules since the PPI surface is usually large, flat, featureless, and without a "pocket" or "groove" for ligand binding. The PCSK9-LDLR PPI interface is such a typical case. In this study, a potential binding pocket was generated on the PCSK9-LDLR PPI surface of PCSK9 through induced-fit docking. On the basis of this induced binding pocket, virtual screening, molecular dynamics (MD) simulation, and biological evaluations have been applied for the identification of novel small molecule inhibitors of PCSK9-LDLR PPI. Among the selected compounds, compound 13 exhibited certain PCSK9-LDLR PPI inhibitory activity (IC50: 7.57 ± 1.40 μM). The direct binding affinity between 13 and PCSK9 was determined with a KD value of 2.50 ± 0.73 μM. The LDLR uptake function could be also restored to a certain extent by 13 in HepG2 cells. This well-characterized hit compound will facilitate the further development of novel small molecule inhibitors of PCSK9-LDLR PPI.

A copper-mediated cyclization and dimerization of indole derived oxime acetate was developed to generate a series of biimidazo[1,2-a]indole scaffolds with two contiguous stereogenic quaternary carbons in one step.

USP7 has been regarded as a potential therapeutic target for cancer. In this study, virtual screening, molecular dynamics (MD) simulation, and biological evaluation have been applied for the discovery of novel USP7 inhibitors targeting the catalytic active site. Among the obtained compounds, compound 12 with a novel scaffold structure exhibited certain USP7 inhibitory activity (Ub-AMC assay IC50 = 18.40 ± 1.75 μM, Ub-Rho assay IC50 = 7.75 μM). The binding affinity between USP7CD (USP7 catalytic domain) and this hit compound was confirmed with a KD value of 4.46 ± 0.86 μM. Preliminary in vitro studies disclosed its antiproliferative activity on human prostate cancer cell line LNCaP with an IC50 value of 15.43 ± 3.49 μM. MD simulation revealed the detailed differences of protein-ligand interactions between USP7CD and the ligands, including the reference compound ALM4 and compound 12, providing some important information for improving the bioactivity of 12. This hit compound will serve as a promising starting point for facilitating the further discovery of novel USP7 inhibitors.

The development of enantioselective desymmetrization of

BMS-986120 is a PAR4 antagonist that is being investigated as an antiplatelet agent in phase I clinical trial. An improved synthesis of BMS-986120 has been developed. Based on the novel synthetic approach to BMS-986120, a series of deuterated derivatives of BMS-986120 have been synthesized and biologically evaluated to search for more potent antiplatelet agents. The in vitro antiplatelet assay by turbidimetry demonstrated that PC-2 and PC-6 had IC50 values of 6.30 nM and 6.97 nM, respectively, versus BMS-986120 with an IC50 of 7.80 nM. The result of in vitro metabolic stability study showed that all of the deuterated compounds had similar half-life (T1/2) and intrinsic clearance (Clint) in comparison with BMS-986120. Further probing the metabolic profile of BMS-986120 is worth being conducted.

An efficient approach to chiral α-hydroxy acid esters by Lewis acid-mediated asymmetric [1,5]-hydride shift and isomerization of 2-(3-pyrroline-1-yl)arylketone acid ester has been achieved in up to 96% yield and 94% ee. This protocol would be applied in the synthesis of chiral α-hydroxy acid derivatives with simplicity and high enantioselectivity.

A copper-mediated cyclization and dimerization of indole derived oxime acetate was developed to generate a series of biimidazo[1,2

Diabetic kidney disease (DKD) is a major feature of the final stage of nearly all cause types of diabetes mellitus (DM). To date, few safe and effective drugs are available to treat. Peroxisome proliferator-activated receptors (PPARs), comprised of three members: PPAR-α, PPAR-δ and PPAR-γ, play a protective role in the DKD through glycemic control and lipid metabolism, whereas systemic activation of PPAR-γ causes serious side-effects in clinical trials. GFT505 is a dual PPAR-α/δ agonist, and the selectivity against PPAR-γ is still to be improved. Sulfuretin has been shown to suppress the expression of PPAR-γ and improve the pathogenesis of diabetic complications. In this study, by hybridizing the carboxylic acid of GFT505 and the parent nucleus of sulfuretin, we pioneeringly designed and synthetized a series of novel dual PPAR-α/δ agonists, expecting to provide a better benefit/risk ratio for PPARs. Of all the synthesized compounds, compound 12 was identified with highly activity on PPAR-α/δ and higher selectivity against PPAR-γ than that of GFT505 (EC50: hPPAR-α: 0.26 μM vs.0.76 μM; hPPAR-δ: 0.50 μM vs.0.73 μM; hPPAR-γ: 4.22 μM vs.2.79 μM). The molecular docking studies also depicted good binding affinity of compound 12 for PPAR-α and PPAR-δ compared to GFT505. Furthermore, compound 12 exhibited an evidently renoprotective effect on the DKD through inhibiting inflammatory process, which might at least partly via JNK/NF-κB pathways in vivo and in vitro. Overall, compound 12 hold therapeutic promise for DKD.

Pentacyclic triterpenes (PTs) are the active ingredients of many medicinal herbs and pharmaceutical formulations, and are well-known for their anti-inflammatory activity. On the other hand, anti-inflammatory effects of AMP-activated protein kinase (AMPK) have recently drawn much attention. In this study, we found that a variety of naturally occurring PTs sapogenins and saponins could stimulate the phosphorylation of AMPK, and identified δ-oleanolic acid (10) as a potent AMPK activator. Based on these findings, 23 saponin derivatives of δ-oleanolic acid were synthesized in order to find more potent anti-inflammatory agents with improved pharmacokinetic properties. The results of cellular assays showed that saponin 29 significantly inhibited LPS-induced secretion of pro-inflammatory factors TNF-α and IL-6 in THP1-derived macrophages. Preliminary mechanistic studies showed that 29 stimulated the phosphorylation of AMPK and acetyl-CoA carboxylase (ACC). The bioavailability of 29 was significantly improved in comparison with its aglycon. More importantly, 29 showed significant anti-inflammatory and liver-protective effects in LPS/D-GalN-induced fulminant hepatic failure mice. Taken together, PTs saponins hold promise as therapeutic agents for inflammatory diseases.

Activation of AMPK emerges as a potential therapeutic approach to metabolic diseases. AdipoRon is claimed to be an adiponectin receptor agonist that activates AMPK through adiponectin receptor 1 (AdipoR1). However, AdipoRon also exhibits moderate inhibition of mitochondrial complex I, leading to increased risk of lactic acidosis. In order to find novel AdipoRon analogues that activate AMPK without inhibition of complex I, 27 analogues of AdipoRon were designed, synthesized and biologically evaluated. As results, benzyloxy arylamide B10 was identified as a potent AMPK activator without inhibition of complex I. B10 dose-dependently improved glucose tolerance in normal mice, and significantly lowered fasting blood glucose level and ameliorated insulin resistance in db/db diabetic mice. More importantly, unlike the pan-AMPK activator MK-8722, B10 did not cause cardiac hypertrophy, probably owing to its selective activation of AMPK in the muscle tissue but not in the heart tissue. Together, B10 represents a novel class of AMPK activators with promising therapeutic potential against metabolic disease.

CuAlxNiCrFe (x = 0.5, 1, 1.5, 2) high-entropy alloys (HEAs) with good high-temperature oxidation resistance were deposited as bond coats via high-speed laser cladding. The microstructure of the CuAlxNiCrFe bond coats exhibited the columnar-to-equiaxed grain transition with increasing Al content. All bond coats generated a uniform and dense aluminum oxide layer and exhibited a low thermally grown oxide (TGO) growth rate after 100 h of oxidation at 1100 °C. During oxidation, CuAl1.5NiCrFe exhibited an extremely low Al diffusion coefficient, and the grain size of CuAlNiCrFe only grew by ~20%.

A highly selective para C-H amination of unprotected phenols with iminoquinone acetals was realized, giving the functional phenols in good to excellent yields. Overall, this transformation is operationally simple, proceeds with readily available phenols, and has wide substrate scope and low catalyst loading. The biarylamine product is stochastically formed via [5,5]-sigmatropic rearrangement of a mixed acetal species which is generated in situ under the reaction conditions.

A high-yielding copper-catalyzed dearomatization reaction of indole from 2-methyl indole-derived oxime acetates was realized, providing access to structurally novel spiro[indoline-3,2’-pyrrolidine] derivatives in 67-98% yields. When the C2-position of the indole was not substituted, aza-carbazole derivatives were obtained in moderate yields. This transformation provided an efficient approach to access nitrogen-containing spiroindolenine and aza-carbazole derivatives with wide substrate scope.

We disclosed a novel water-soluble photocatalyst that could promote aerobic oxidative hydroxylation of arylboronic acids to furnish phenols in excellent yields. This transformation uses visible-light irradiation under environmentally friendly conditions, that is, water-soluble catalyst, metal-free, green oxidant, room temperature.

The [1,5]-hydride shift/cyclization process as a new Csp³–H bond functionalization has made tremendous advances over the past decades. Herein, we describe reaction pathways for a [1,5]-hydride shift that is triggered by acid. In these transformations, the diene isoindoles are generated in situ and undergo a reaction with different dienophiles to provide access to a series of bridged-ring heterocycles and polycycles in good yields (up to 94 %). In addition, we found that the choice of acid played a critical role and could be used to control the structure of the final product.

A formal [3 + 3] cyclization reaction of 2-indolylmethanols with quinones was realized to furnish indole-fused scaffolds in moderate to excellent yields. This protocol was proceeded smoothly under acid condition, with high high yields and broad substrate scope.

International audience; A set of fifteen 2-naphthol-derived atropisomers were evaluated on three different cyclofructan-based chiral stationary phases (CSP). The cyclofructan CSPs were a dimethylphenyl-derivatized cyclofructan 7 (CF7-DMP), a isopropyl (CF6-P) and a R-naphthylethyl cyclofructan 6 (CF6-RN) derivative, all bonded to 5-mu m spherical fully porous silica particles packed into three 25cmx4.6mm columns (commercially available as Larihc columns). The 15 atropisomers were analyzed in the normal-phase mode with heptane/alcohol mobile phases. The CF7-DMP column was the most effective partially or fully separating 14 of the 15 compounds (93%). All 15 compounds could be separated by at least one cyclofructan column. Five compounds could be partially or fully separated by all three CSPs. The effect of ethanol, 2-propanol and butanol as 5 and 10% v/v polar modifiers in heptane was studied. A prototype 15cmx4.6mm column packed with superficially porous 2.7 mu m CF6-P bonded particles was tested with the same set of compounds and a standard HPLC system. The increased efficiency and solvent saving were significant.

Bridged indoline derivatives were synthesized by an intermolecular Pd-catalyzed allylic dearomatization reaction of substituted indoles. The reaction between indoles and allyl carbonates bearing a nucleophilic alcohol side-chain proceeds in a cascade fashion, providing bridged indolines in excellent enantioselectivity.

An intramolecular palladium(II)-catalyzed dearomative arylation reaction of indoles via CH bond functionalization was developed, providing access to structurally novel spiroindolenines with moderate to good yields. A one-pot process for the synthesis of spiroindoline derivatives was also realized.

Herein we disclose a scalable organo-catalytic direct arylation approach for the regio- and atroposelective synthesis of non-C2-symmetric 2,2′-dihydroxy-1,1′-binaphthalenes (BINOLs). In the presence of catalytic amounts of axially chiral phosphoric acids, phenols and naphthols are coupled with iminoquinones via a cascade process that involves sequential aminal formation, sigmatropic rearrangement, and rearomatization to afford enantiomerically enriched BINOL derivatives in good to excellent yields. Our studies suggest that the (local) symmetry of the initially formed aminal intermediate has a dramatic impact on the level of enantioinduction in the final product. Aminals with a plane of symmetry give rise to BINOL derivatives with significantly lower enantiomeric excess than unsymmetrical ones featuring a stereogenic center. Presumably asymmetric induction in the sigmatropic rearrangement step is significantly more challenging than during aminal formation. Sigmatropic rearrangement of the enantiomerically enriched aminal and subsequent rearomatization transfers the central chirality into axial chirality with high fidelity.

Key message ‘Newhall’ grafted onto xiangcheng rootstock withGlomus versiformeor without displayed different responses, and genes related to photosystem II and alpha-linolenic acid metabolism pathways were involved in the responses.

The Rh(ii)-catalyzed sulfur ylide [1,2]-rearrangement of carbenoids generated from aryldiazoacetates has been realized via N-S bond insertion, generating tertiary sulfides in moderate to excellent yields. This demonstrates the first use of the sulfur ylide [1,2]-rearrangement undergoing N-S bond insertion. This protocol could proceed smoothly with high regioselectivity, low catalyst loading (0.1 mol% Rh2(OAc)4), gram-scale reaction and broad substrate scope. And the product could be converted into glycine derivatives through simple procedures.

A promising new bond coat using CuAlNiCrFe high-entropy alloy was proposed in this paper. The difference in pre-oxidation conditions between the traditional thermal-sprayed MCrAlY bond coat and CuAlNiCrFe high-entropy alloy bond coat deposited using high-speed laser cladding was investigated. The result confirmed that the CuAlNiCrFe high-entropy alloy bond coat deposited using high-speed laser cladding can complete the pre-oxidation faster and form a continuous α-Al2O3 thermally grown oxide (TGO), which shortens the initial oxidation stage, thereby avoiding the formation of other oxides and spinel structures. In the subsequent isothermal oxidation process, the block-like structure of the high-speed laser cladding layer and the sluggish diffusion effect of the high-entropy alloy work together to ensure the slow and continuous supply of aluminum element to TGO layer and obtain a low growth rate. Also, the diffusion between the bonding layer and the substrate is controlled at a low level, and the new CuAlNiCrFe bond coat exhibits excellent oxidation and diffusion resistance. With the consumption of aluminum, the phase structure of the high-entropy alloy bond coat changed from BCC to FCC, but it still maintained a stable simple solid solution structure.

USP7 as a deubiquitinase plays important roles in regulating the stability of some oncoproteins including MDM2 and DNMT1, and thus represents a potential anticancer target. Through comparative analysis of USP7 co-crystal structures in complex with the reported piperidinol inhibitors, we noticed that the USP7 Phe409 sub-site might have good adaptability to the ligands. Based on this observation, 55 N-aromatic and N-benzyl piperidinol derivatives were designed, synthesized and biologically evaluated, among which compound L55 was identified as a highly selective and potent USP7 inhibitor (IC50 = 40.8 nM, KD = 78.3 nM). X-ray crystallographic studies revealed that L55 bound to USP7 with a new pose that was very different from the previously reported inhibitors. The results of cellular assays showed that L55 had strong antitumor activity against LNCaP (IC50 = 29.6 nM) and RS4; 11 (IC50 = 41.6 nM) cells, probably through inducing cell death and restricting G0/G1 and S phases. Moreover, L55 dose-dependently reduced the protein levels of MDM2 and DNMT1 and increased the protein levels of p53 and p21. These findings could have valuable implications for designing novel structural classes of USP7 inhibitors.

This paper presents a novel obstacle-surmounting robot with eight big wheels, which is designed for searching and rescuing tasks in cities. Four passive planetary swing wheel structures, each of which is composed of two wheels and a planetary structure, are installed into four corners of the vehicle symmetrically. The planet carrier performs as a swing arm to adjust the relative angle of the vehicle' chassis and ground automatically and passively. Consequently, the necessary actuators for the vehicle are reduced to four. For enhancing the stability and adaptability against complex uneven terrain, analysis and simulation experiments have been done to optimize dimensions of the vehicle, where the diameter of the wheel and the central distance of the neighbor planetary sets are modified to 460 mm and 560 mm in the end. Finally, experimental results demonstrate excellent stability and adaptability of the vehicle, and the vehicle is easy to control without any additional operations.

A Bronsted acid catalyzed redox-annulated cascade reaction between 2-arylpyrroles and 2-(pyrrolidin-1-yl)-, 2-(piperidin-1-yl), or 2-morpholinobenzaldehydes has been developed. This dehydration/1,5-hydride shift/cyclization sequence results in the construction of two new C(sp2)–C(sp3) bonds, providing structurally diverse 1,2-pyrrole-annulated benzazepines in yields of 25–65 %.

Expeditious access to oxadiazepines via 1,5-hydride shift/cyclization of pyrrolidine- or tetrahydroisoquinoline-containing nitrones has been developed. With 1,3-dipole nitrones serving as the hydride acceptors, this transformation was promoted by a Lewis acid, providing access to structurally diverse oxadiazepines in good yields. A one-pot process for in situ nitrone formation, a 1,5-hydride shift, and ring cyclization was also realized.

Chronic constipation is a common gastrointestinal disease severely affecting the patient׳s quality of life. The traditional treatment of constipation is the use of laxatives. Recently, several new drugs including lubiprostone, linaclotide and prucalopride have been approved for treatment of chronic constipation. However, a significant unmet medical need still remains, particularly among those patients achieving poor results by current therapies. The 5-HT4 receptor modulators velusetrag and naronapride, the guanylate cyclase C agonist plecanatide and the ileal bile acid transporter inhibitor elobixibat are recognized as the most promising drugs under investigation. Herein, we give a comprehensive review on the pharmacological therapeutics for the treatment of chronic constipation, with the purpose of reflecting the drug development trends in this field., Graphical abstract Chronic constipation is a common gastrointestinal disease severely affecting the patient׳s quality of life. Herein, we give a comprehensive review on the pharmacological therapeutics for the treatment of chronic constipation, with the purpose of reflecting the drug development trends in this field.

A general method to synthesize N -aryl pyrrole derivatives was realized via the reactions of 2-(3-pyrroline-1-yl)arylaldehydes with indoles under acidic conditions, which underwent [1,5]-hydride shift/isomerization process. The desired products could be obtained in good to high yields with a wide substrate scope.

A practical method to synthesize N-aryl pyrrole derivatives involving O-alkylated quinone methides as hydride acceptors has been developed via [1, 5]-hydride shift/isomerization cascade under acidic condition. The desired product could be obtained in moderate to good yields with broad substrate scope.

A concise synthesis of spiroindolenines from 2-substituted (Me, Et) indoles and 2-(pyrrolidin-1-yl)benzaldehydes has been developed via a [1,5]-hydride shift/cyclization sequence. This method features a wide substrate scope and an operationally simple procedure, affording the spiroindolenines in good to excellent yields and moderate diastereoselectivity (3.5/1 dr). When the inseparable mixture of spiroindolenine isomers were washed with isopropyl ether after flash chromatography, the major isomers could be obtained in up to >20/1 dr.

A formal [4 + 2] cycloaddition reaction of 1,3-disubstituted indoles and alkylquinones was realized to furnish polycyclic indolines in good yields. This protocol proceeded smoothly under basic conditions, with high atom-economy and broad substrate scope.

A novel Ugi-type reaction triggered by 1,5-hydride shift has been established, giving access to N-arylprolinamides and related compounds in high atom economy and good yields. This is an example of a two starting material–three component reaction. The benzyl alcohol substrate 1 acts as a dual synthon, which upon treatment with a Bronsted acid affords iminium ion and water. Nucleophilic attack at the iminium ion by the third component isocyanide, followed by hydrolysis with the endogenic water, gives the Ugi-type reaction products. The reaction proceeds under mild conditions and is tolerable to a broad scope of substrates.

A practical asymmetric synthesis of 3,4-disubstituted proline derivatives has been realized with high stereoselectivity and moderate yield. The key steps involved are desymmetric ring-opening reaction of commercially available anhydrides, intramolecular Strecker reaction and thermodynamically controlled cyanide hydrolysis. Based on this methodology, the synthesis of HCV protease inhibitor Telaprevir was achieved.

An efficient approach to synthesize N-aryl pyrroles via Lewis acid-mediated 1,5-hydride shift and isomerization of 2-(3-pyrroline-1-yl)arylaldehydes has been achieved in up to 89% yield. This methodology is applicable to the synthesis of fluorazene derivatives as electron donor (D)/acceptor (A) molecules.

Live testing of resistive current of metal oxide arrester (MOA) and on-line monitoring of capacitive current of capacitor voltage transformer or casing tube (CT) are two important parameters for stable and safe operation of power system. The present method is to separately monitor these two types of equipment. Through analyzing equipment structure, monitoring principle, integration mechanism and so on, this article realizes combined measurement of resistive current and capacitive current. Thus, the combined monitoring of metal oxide arrester (MOA), rheology and CT insulation status is achieved.

Unadorned Aziridines Multiple catalytic methods have been developed to make aziridines—strained triangular carbon-nitrogen-carbon rings that function as versatile synthetic intermediates. However, the majority require protection of the nitrogen precursor with a sulfonyl group that is subsequently inconvenient to remove. Jat et al. (p. 61 ; see the Perspective by Türkmen and Aggarwal ) used a hydroxylamine derivative as the nitrogen source together with an established rhodium catalyst to prepare a wide range of unprotected aziridines, with nitrogen bonded simply to hydrogen or a methyl group.

Herein we report a highly enantioselective synthesis of polycyclic indoles and pyrroles with up to 99% ee by an iridium catalyst system consisting of a commercially available iridium precursor and a readily accessible ligand. Investigation of the reaction mechanism led to the discovery of an unprecedented dearomatized spiro intermediate and its in situ migration phenomenon. The new reaction mode features switching of the substituent from the indole C-3 position to the C-2 position (from the C-2 position to the C-3 position in the case of pyrrole) without loss of the enantiomeric purity, providing a novel concept in designing the asymmetric construction of enantiopure polycyclic indoles and pyrroles.

Short circuit impedance test is one of the important methods for the transformer winding distortion diagnose. At present the test current is too low when we using short circuit impedance method. Upon the understanding for electrical properties of the transformer we developed a device with test current up to 10 Ampere, and combined longitudinal comparison method and lateral comparison method as our criterion algorithm. The device we developed matches the requirements of related standards. It comes in a complete set and fits on-site application. Through three practical examples we can see the improvement of the current is effective for the test accuracy in the transformer winding distortion diagnose.

Diverse indole-based peri-annulated compounds were synthesized via transition-metal-catalyzed allylic alkylation reaction. With palladium catalyst, indole-based nine-membered ring products were obtained in 40–70% yields. When iridium catalyst was used, highly enantioenriched seven-membered ring products were obtained in 40–78% yields and 91–97% ee. Meanwhile, when 3-substituted indole substrates were employed with a palladium catalyst, asymmetric allylic dearomatization of indoles occurred with products obtained in 48–78% yields and 35–78% ee with a chiral ferrocene-based Phox ligand. Interestingly, with an iridium catalyst, Friedel–Crafts type allylic alkylation reaction proceeded at the C5 position of indole, affording the products with 40–60% yields and 56–97% ee.