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961.
    
Nickel-base alloys have been selected as a potential metallic material for reactor internals in Generation IV reactors. In order to evaluate their helium embrittlement resistance, microstrain changes and evolution of vacancy-type defects after Helium irradiation and postimplantation annealing have been studied by grazing incidence X-ray diffraction (GIXRD) and slow positron doppler broadening spectroscopy (PDB). GIXRD results show that the increase in microstrain after helium irradiation is more pronounced at high doses. The observed S parameters of PDB increase with the irradiation doses, which indicates a significant number of vacancy-type defects, possibly helium-vacancy clusters. For postimplantation annealing specimens, the microstrain characterized by GIXRD has recovered. The surprise is the S parameters that significantly increase, revealing that helium atoms trapped at unstable helium-vacancy clusters desorb during annealing, contributing to the growth of helium bubbles. These findings of microstrain mechanisms and vacancy-type defects behaviors give us new insights into the helium irradiation evaluation.  相似文献   
962.
    
Electrocatalysis based on metal–organic coordination polymers (CPs) catalyst, especially metal-1,1,2,2-ethenetetrathiolate (ett), has received increasing attention due to their high-electrical conductivity, unique morphology and excellent redox activity. Here, amorphous powder of CPs is synthesized and firmly coated on the surfaces of carbon fiber cloth (CFC), then serves as active electrocatalyst for hydrogen evolution reaction (HER). The operating overpotentials of the poly[Kx(M-ett)] (Co, Ni or Cu) are 0.43, 0.36, 0.45 V, respectively, at a current density of 10 mA cm−2 with pH = 0, along with the Tafel plot of 144, 153, 329 mV dec−1. Moreover, they show remarkable electrolysis stability under harsh acid conditions. This study extends the HER application of poly[Kx(M-ett)] coating on CFC surfaces.  相似文献   
963.
    
We designed, synthesized, and characterized a tri-block copolymer. Its hydrophobic part, a chain of histone deacetylase inhibitor (HDACi) prodrug, was symmetrically flanked by two identical PEG blocks, whereas the built-in HDACi was a linear molecule, terminated with a thiol at one end, and a hydroxyl group at the other. Such a feature facilitated end-to-end linkage of prodrugs through alternatively aligned disulfides and carbonates. The disulfides served dual roles: redox sensors of smart nanomedicine, and warheads of masked HDACi drugs. This approach, carefully designed to benefit both control-release and efficacy, is conceptually novel for optimizing drug units in nanomedicine. Micelles from this designer polyprodrug released only PEG, CO2 and HDACi, and synergized with DOX against HCT116 cells, demonstrating its widespread potential in combination therapy. Our work highlights, for the first time, the unique advantage of thiol-based drug molecules in nanomedicine design.  相似文献   
964.
    
Copper(I) halide organic-inorganic hybrid luminescent materials have many advantages, such as diverse structure, facile synthesis, high luminescent efficiency, tunable optical performance, etc., and show a broad application prospect in energy-saving lighting, display and other fields. However, compared with commercial rare-earth-metal-based phosphors, the reported hybrids generally suffer from poor stability and low luminescent efficiency, which are the bottleneck problem of their practical application. With the aim of developing high-performance organic-inorganic hybrid luminescent materials, a new synthesis strategy has been reported. This strategy can systematically design and synthesis copper(I) halide ionic hybrid structures by combining the covalent bonding and ionic bonding between inorganic and organic components into one structure, and use their synergistic effect to optimizing their properties. This design method is expected to develop high-performance organic-inorganic hybrid luminescent materials, promote the in-depth understanding of this field, and provide new ideas for the optimization of other types of hybrid materials.  相似文献   
965.
    
Red deer (Cervus elaphus) blood is widely used as a health product. Mixed culture fermentation improves the flavor and bioavailability of deer blood (DB), and both DB and its enzymatic hydrolysates exhibit anti-fatigue activities in vivo. To elucidate the bioactive ingredients, enzymatic hydrolysates were fractioned into different peptide groups using reversed phase resin chromatography, and then evaluated using an exhaustive swimming mice model to assess swimming time and biochemical parameters. The structures of the bioactive peptides were elucidated by high performance liquid chromatography with tandem mass detection. Thirty-one compounds were identified as glutamine or branched-chain amino acids containing short peptides, of which Val-Ala-Asn, Val-Val-Ser-Ala, Leu(Ile)-Leu(Ile)-Val-Thr, Pro-His-Pro-Thr-Thr, Glu-Val-Ala-Phe and Val-Leu(Ile)-Asp-Ala-Phe are new peptides. The fractions containing glutamine or valine short peptides, Ala-Gln, Val-Gln, Val-Val-Ser-Ala, Val-Leu(Ile)-Ser improved exercise endurance by increasing hepatic glycogen (HG) storage. The peptides group containing Leu(Ile)-Leu(Ile), Asp-Gln, Phe- Leu(Ile), Val-Val-Tyr-Pro contributed to decreased muscle lactic acid (MLA)accumulation and to an increase in HG. The anti-fatigue activities of DB hydrolysates were attributed to the synergistic effects of different types of peptides.  相似文献   
966.
    
An ascorbic acid (AA) electrochemical sensor was fabricated by ferrocene methanol (Fc−OH) modified multi-walled carbon nanotube yarn (CNTY). The prepared sensor (Fc−OH/CNTY) exhibited outstanding flexibility, highly stretchability, excellent bendability and obviously electrocatalytic activity for oxidation of ascorbic acid. The morphology of Fc−OH/CNTY was evaluated by scanning electron microscope. The electrochemical behaviour of Fc−OH/CNTY sensor was studied by cyclic voltammetry and amperometry measurements. Moreover, the influence of Fc−OH concentration, applied potential and electrolyte solution pH were also investigated to obtain the best sensor performance. The prepared sensor exhibited a wide linear range from 3 μM to 3.0 mM toward AA, and a detection limit of 1.32 μM (S/N=3). It also possessed a good lifetime and a fast response speed (2.83 s). In addition, the Fc−OH/CNTY sensor remained 90 % and 60 % of its initial activity after 100 and 500 times bending, respectively, which indicated a potential application on flexible, implantable and/or wearable electrochemical sensors.  相似文献   
967.
    
Armeniaca mume Sieb. blossom is among the traditional Chinese edible flowers, and it is widely used in the food and pharmaceutical industries. Flavonoids are among the most abundant bioactive compounds in A. mume Sieb. blossom. However, the research on the extraction of flavonoids from A. mume Sieb. blossom and their immunomodulating function is insufficient. In this study, we developed a microwave-assisted enzymatic extraction of flavonoids from A. mume Sieb. blossom (FAMB) and explored their immunomodulating effect on mice with dextran sulfate sodium salt-induced colitis. The results showed that the optimum parameters for microwave-assisted enzymatic extraction of FAMB were as follows: cellulase: 2.0%; microwave power: 200 W; microwave action time: 5 min; and enzymatic hydrolysis time: 50 min. FAMB significantly promoted the lymphocyte proliferation and natural killer (NK) cell killing activity in colitis mice, and increased the concentrations of TNF-α, IFN-γ, and IL-2 in serum. FAMB also significantly reduced the apoptosis of spleen lymphocytes in these mice. These results demonstrated that the microwave-assisted enzymatic method could significantly improve the yield and efficacy extraction of FAMB. FAMB showed a good immunomodulation effect on colitis mice.  相似文献   
968.
    
The construction of an isoquinoline skeleton typically starts with benzene derivatives as substrates with the assistance of acids or transition metals. Disclosed here is a concise approach to prepare isoquinoline analogues by starting with pyridines to react with β-ethoxy α,β-unsaturated carbonyl compounds under basic conditions. Multiple substitution patterns and a relatively large number of functional groups (including those sensitive to acidic conditions) can be tolerated in our method. In particular, our protocol allows for efficient access to tricyclic isoquinolines found in hundreds of natural products with interesting bioactivities. The efficiency and operational simplicity of introducing structural complexity into the isoquinoline frameworks can likely enable the collective synthesis of a large set of natural products. Here we show that fredericamycin A could be obtained via a short route by using our isoquinoline synthesis as a key step.

A concise approach for rapid assembly of multicyclic isoquinoline scaffolds from pyridines and β-ethoxy α,β-unsaturated carbonyl compounds was developed, which enabled the formal total synthesis of fredericamycin A.

Isoquinolines and their derivatives are common structural motifs in numerous natural products. Among them, the analogues of isoquinolines fused with rings from the benzene side such as 8-hydroxyisoquinolin-1[2H]-one (Fig. 1a) have been found in hundreds of natural products with interesting bioactivities.1 For example, fredericamycin A and the related family members, isolated from Streptomyces griseus, show both antimicrobial and anti-tumor activities.2 Ericamycin is a natural product isolated in the culture of Streptomyces varius n. sp. with anti-staphylococcal activities.3 Due to the widespread presence of isoquinolines in both natural and synthetic molecules, numerous approaches have been developed to assemble this class of scaffolds.4 The dominated strategies reported to date focus on forming the new pyridine ring of isoquinolines (Fig. 1b, left part). Classic methods include Bischler–Napieralski isoquinoline synthesis,4a,b Pictet–Gams isoquinoline synthesis,4a and Pomeranz–Fritsch reaction.4a These reactions, proven to be useful since as early as 1893,5 have their own merits and limitations. For instance, high reaction temperature (e.g. reflux in toluene) and strong acids are typically required and thus functional group tolerance can become challenging. On the other side, the introduction of structural complexities and substitution patterns is constrained as the substrates have to be pre-settled to favor the formation of pyridine moieties. Here we report a new approach to prepare isoquinoline scaffolds by constructing a new benzene ring (Fig. 1b, right part).6 Our method starts with pyridine derivatives as the substrates to react with readily available β-ethoxy α,β-unsaturated carbonyl compounds. The reaction cascade involves five main plausible mechanistic processes (Michael addition, Dieckmann condensation, elimination, aromatization and in situ methylation) to furnish isoquinoline-based products with medium to good yields. The tricyclic isoquinoline-containing products might serve as formal common starting points for rapid total synthesis of a large number of natural products, such as those exemplified in Fig. 1a. In the present study, we demonstrate that starting from the tricyclic isoquinoline adduct 6a prepared using our method, fredericamycin A can be synthesized in 8 steps (Fig. 1c). Our strategy for isoquinoline assembly offers complementary and in certain cases better solutions not readily provided by the classic methods. We expect our method to find impressive applications in concise modular synthesis of complex natural products and molecular libraries, especially those bearing isoquinoline units fused with additional cyclic structures.Open in a separate windowFig. 1Isoquinoline analogues and their synthesis.Our design and initial studies are illustrated in Scheme 1.7 We first used pyridine 1a to react with α-substituted cycloenones (2a–2d), in the hope of obtaining isoquinoline 3a as the target product (Scheme 1a). The use of 2a and 2b was inspired by studies from Tamura, in which α-Br in 1,4-naphthoquinone was used as a leaving group to form an aromatic ring.8 Unfortunately, no product was formed and most of the starting materials were recovered. When SPh (2c) or SOPh (2d) was incorporated at the α site of the cycloenone, side products 4a and 4b were isolated respectively in moderate yields. The Michael products 4a and 4b could not be further transformed into our desired cyclic product 3a under various conditions. We then studied the use of β-substituted cycloenones (2e–2g) to react with 1a (Scheme 1b). No reactions were observed when 2e or 2f was used. To our delight, when the halogen of 2e/2f was replaced with a methoxy unit (OCH3, substrate 2g), an encouraging amount of annulation product 3a was detected (10% yield). A side product 5a was also obtained (5% yield) in this initial study and it couldn''t be further transformed into the annulation product 3a under various alkaline conditions. It is noteworthy that, while β-alkoxy cycloenones (specifically, only β-alkoxy cyclohexenones) have been used in Staunton–Weinreb annulation9 to prepare fused aromatic compounds, no examples for those containing a heterocyclic aromatic ring were reported.10 Even for the construction of an aromatic ring without any heteroatom, low yields (mostly ranging from 0 to 30%) often occurred for this type of annulation starting with β-alkoxy cycloenones,9 which severely hampered its usage in Staunton–Weinreb annulation for the total synthesis of natural products. Our initial results showcased the possibility of direct assembly of isoquinoline scaffolds from β-methoxy cyclopentenone for the first time, though also in a low yield of 10%.Open in a separate windowScheme 1Proposed routes and initial studies for isoquinoline synthesis.With the initial results in hand, we performed additional condition optimization (Table 1). The best conditions (Table 1, entry 1) involve the deprotonation of 1a with LDA at −78 °C, warming the reaction mixture to room temperature in 10 minutes after the completion of slow addition of 2h, and most importantly, in situ methylation of the hydroxyl group of phenol 3a, which accounts for the relatively high yield of adducts 6a (72% yield). Without methylation, the phenol adduct 3a was isolated only in 14% yield (entry 2).11 The β-methoxy cyclopentenone 2g could also react to give 6a in a lower yield of 65% (entry 3). Other bases [such as triethylenediamine (DABCO), diazabicyclo[5.4.0]undec-7-ene (DBU), 4-dimethylaminopyridine (DMAP), lithium bis(trimethylsilyl)amide (LiHMDS) and potassium bis(trimethylsilyl)amide (KHMDS)] gave poorer results with yields ranging from 0 to 42% (entry 4). When THF was changed to other solvents, lower yields (<41%) were obtained (entry 5). Revising the ratio of 1a to 2h from 1 : 1.5 to 1.5 : 1 delivered 6a in 39% to 54% yields (entries 6–8). Lower reaction temperature (e.g. −78 °C) could not improve the outcome of this cascade transformation, but gave 23% yield of 6a together with 16% yield of recovered starting material 2h (entry 9). Long exposure to low temperature in step 1 could also lead to a considerable amount of the undesired elimination product 5a (ca. 29% yield), which was decomposed under the following methylation conditions (step 2). No product was observed in the absence of the methoxy group in 1a as it could stabilize the transition state via the formation of a metallate complex (entry 10).Screening of conditionsa
EntryVariation from standard conditionsYieldb (%)
1None72
2Without methylation14
3OCH3 instead of OEt in 2h65
4DABCO, DBU, DMAP, LiHMDS and KHMDS instead of LDA0–42
5Other solvents in step 1<41
6 1a : 2h = 1 : 139
7 1a : 2h = 1.5 : 154
8 1a : 2h = 1 : 1.542
9c−78 °C for step 123
10H instead of OCH3 in 1a0
Open in a separate windowaStandard conditions: 1a (0.2 mmol) and LDA (0.2 mmol) reacted in THF at −78 °C for 1 h; 2h (0.1 mmol) was added dropwise to the mixture before warming up to rt in 10 min. The reaction was quenched by the addition of saturated aqueous solution of NH4Cl after completion monitored by TLC. After the removal of solvents, the crude residue was treated directly with TBAB (0.2 eq.), NaOH (2.0 eq.) in water (1 mL), and Me2SO4 (4.0 eq.) in CH2Cl2 (1 mL).bIsolated yield.cRecovered starting material 2h: 16% yield.With the optimal reaction conditions in hand, we next examined the scope of the pyridine derivatives 1. As we can see from Scheme 2, substrates with the aliphatic substituents at C3 could afford the corresponding tricyclic isoquinoline products (6a and 6b) in acceptable yields. Besides, the incorporation of an aromatic ring at this site (6c–6j) also works well for this transformation, wherein electron-rich aromatic rings (6c–6g) could give higher yields than the corresponding electron-deficient ones (6h–6j). It should be noted that the relatively lower yield of 44% for 6h was partially due to the slow reaction rate as the recovered starting material was always detected in this transformation. When it comes to C4 substitution, the isoquinoline products with broad structural diversities such as alkyl (6k), alkenyl (6l–6n),12 alkynyl (6o), benzyl derivatives with different substituents on the phenyl ring (6p–6t), heteroaromatic ring (6u) and thioether (6v) could be obtained in 57–93% yields. Moreover, substrates bearing acid-hydrolyzable functionalities (6w) and with a relatively bulky secondary substituent (6x) also worked well under the optimized reaction conditions. Next, we examined the possibility of introducing a side chain at C5. To our delight, the substrate with an ethyl group instead of the methyl group on the aromatic ring reacted smoothly to deliver the corresponding isoquinoline 6y in 89% yield. Further study revealed that the exposure of the bicyclic substrate 5,6,7,8-tetrahydroisoquinoline derivative to the optimized reaction conditions could furnish the polycyclic product 6z in 92% yield. Finally, we relocated the nitrogen atom in the pyridine ring. The experimental results indicated that the substrate with nitrogen atom located at C3 can''t react to form the corresponding isoquinoline 6aa, possibly due to the mismatched dipole orientation. When the nitrogen atom was sited at the ortho-position of the methyl group in the aromatic ring, quinoline 6ab could not be detected either under the optimized reaction conditions. The control experiments showcased the decisive influence of the location of nitrogen atom in the aromatic ring on the reactivity of this cascade transformation.Open in a separate windowScheme 2Scope of pyridine derivatives.For the five-membered cycloenone derivatives 2 (Scheme 3), substrates with different substituents at the α′ position work well for this transformation (6ac–6ak),12 of which the incorporation of a quaternary carbon center (6aj) and a heteroatom (6ak) at this site was included. The introduction of an allyl group at the β′ position in cyclopentenone proved to be viable for this transformation, delivering 6al in 64% yield. More encouragingly, when the sterically hindered substrate with a quaternary carbon center located at the γ site was exposed to the optimized reaction conditions, the isoquinoline 6am was obtained in 65% yield. This is challenging, considering the fact that the reacting site is just adjacent to a sterically bulky all-carbon quaternary stereocenter. Bicyclic 3-ethoxy-1H-inden-1-one is also suitable for this cascade transformation, giving the tetracyclic 10H-indeno[1,2-g]isoquinolin-10-one derivative 6an in 89% yield. When it comes to six-membered cycloenone derivatives (6ao–6au), substrates with substituents at α′ and β′ positions all worked smoothly to provide the corresponding isoquinoline products in moderate to high yields. Notably, Kita reported a 5-step reaction sequence to get the tricyclic benzo[g]isoquinoline-derived product 6as starting from the 1a analogue in an overall yield of 22%.6b Using our developed method, 6as could be easily obtained in 53% yield from 1a. Unexpectedly, a side product 6av was isolated in moderate yield when it comes to the γ-substituted substrate. Further study revealed that cyclohept-2-en-1-one with a medium-sized ring (6aw), lactone (6ax), and lactam (6ay) all worked well for this annulation cascade, which significantly expanded the substrate scope of this powerful cascade transformation.Open in a separate windowScheme 3Scope of cycloenone derivatives and more.Finally, fredericamycin A was selected further as the target molecule to verify the flexibility of our method in the total synthesis of natural products, especially those containing 8-hydroxyisoquinolin-1[2H]-one units.13 Since its first isolation in 1981, fredericamycin A attracted much attention from the synthetic community due to its interesting chemical structure and significant anti-tumor activity.2,14,15 The synthetic route was inspired by the expeditious work from Bach.16a As shown in Scheme 4, we started our synthetic attempts with our developed multifold reaction sequence of pyridine 1a and β-ethoxy enone 2h, delivering the corresponding methyl ether 6a on a gram scale. To the best of our knowledge, this is the first example of isoquinoline synthesis directly starting from a pyridine derivative in a single step. The aromatic ketone 6a was subjected to a Mukaiyama aldol/pinacol rearrangement cascade with cyclobutene 7 to give spiro diketone 8 in 42% yield.7,16 After oxidation with DDQ, the pivotal synthon 9 was obtained in 62% yield.7 It should be noted that the addition of p-TsOH is necessary for this transformation as a sluggish reaction rate was detected in the absence of an acid. Meanwhile, a four-step access of phthalidyl chloride 10 was developed starting from a commercially available benzoic acid derivative.7,17 For the crucial Hauser–Kraus annulation18 between fragments 9 and 10, we found that the coupling product 11 was not stable and thus protected directly as the corresponding methyl ether. After extensive screening of reaction conditions,7 LiOtBu turned out to be the only efficient base for this annulation. Mechanistically, the intermolecular Michael addition of segments 9 and 10 was followed by successive transformations involving Dieckmann condensation of enolate V, extrusion of chloride anions from the diketone VI, and last aromatization of the advanced intermediate VII to afford the hexacyclic diphenol 11 with the full skeleton embedded in fredericamycin A. As far as we know, this is the first example of 3-halophthalide as the Hauser donor instead of the classic sulfonyl- or cyano-containing substrates in Hauser–Kraus annulation, as 3-halophthalide was previously reported not suitable for this annulation.18aIn situ methylation of the newly formed phenol hydroxyls delivered Kita''s intermediate 12 in 51% yield in 2 steps. A further 4-step sequence ensured the accomplishment of fredericamycin A.19 The overall synthetic route clearly showcased the power of ingenious introduction of multifold reaction cascades to realize the best performance from the point of step economy.Open in a separate windowScheme 4Formal synthesis of fredericamycin A.  相似文献   
969.
    
Given a bounded strongly pseudoconvex domain D in with smooth boundary, we characterize ‐Bergman Carleson measures for , , and . As an application, we show that the Bergman space version of the balayage of a Bergman Carleson measure on D belongs to BMO in the Kobayashi metric.  相似文献   
970.
In 1960, Baumslag, following up on work of Cernikov for the 1940s, proved that a hypercentral p-group G with G = G p is a divisible Abelian group. In this article, we provide an interesting generalization of this 45 year old result: If a hypercentral p-group G satisfies |G:G p |<∞ (of course, it contains G = G p ), there exists a normal divisible Abelian subgroup D such that |G:D|<∞.  相似文献   
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