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1.
Artigo em Inglês | MEDLINE | ID: mdl-33826200

RESUMO

The first catalytic asymmetric multiple vinylogous addition reactions initiated by Meinwald rearrangement of vinyl epoxides were realized by employing chiral N,N'-dioxide/Sc(III) complex catalysts. The vinyl epoxides, as masked ß,γ-unsaturated aldehydes, via direct vinylogous additions with isatins, 2-alkenoylpyridines or methyleneindolinones, provided a facile and efficient way for the synthesis of chiral 3-hydroxy-3-substituted oxindoles, α,ß-unsaturated aldehydes and spiro-cyclohexene indolinones, respectively with high efficiency and stereoselectivity. The control experiments and kinetic studies revealed that the Lewis acid acted as dual-tasking catalyst, controlling the initial rearrangement to match subsequent enantioselective vinylogous addition reactions. A catalytic cycle with a possible transition model was proposed to illustrate the reaction mechanism.

2.
Org Lett ; 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33769054

RESUMO

A highly enantioselective three-component reaction of ynamides with carboxylic acids and 2,2'-diester aziridines has been realized by using a chiral N,N'-dioxide/Ho(OTf)3 complex as a Lewis acid catalyst. The process includes the formation of an α-acyloxyenamide intermediate through the addition of carboxylic acids to ynamides and the following enantioselective nucleophilic addition to in-situ-generated azomethine ylides induced by the chiral catalyst. A range of amino acyloxyenamides are delivered in moderate to good yields with good ee values. In addition, a possible catalytic cycle with a transition model is proposed to elucidate the reaction mechanism.

3.
Chemistry ; 2021 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-33749905

RESUMO

A chiral N,N' -dioxide-nickel(II) complex-catalyzed asymmetric amination reaction of 3-bromo-3-substituted oxindoles with anilines was developed. A series of alkyl or aryl 3-amino-indolinones with quaternary stereocenters were obtained in high yields with excellent ee values in one step (up to 99% yield, up to 96% ee). The method provided a readily route to optically active intermediates of 3-amino-2-oxindole-based bioactive compounds. Besides, a possible transition state model was proposed to elucidate the origin of the chirality induction based on the X-ray crystal structure of the catalyst and the adduct.

4.
J Nanosci Nanotechnol ; 21(9): 4615-4624, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-33691840

RESUMO

Based on the migratory phenomenon of the puffer and the cone-shaped structures on its skin, the effects of spinal height and tilt angle on the drag reduction characteristics is presented by numerical simulation in this paper. The results show that the trend of total drag reduction efficiency changes from slow growth to a remarkable decline, while the viscous drag reduction efficiency changes from an obvious increase to steady growth. The total and viscous drag reduction efficiencies are 19.5% and 31.8%, respectively. In addition, with the increase in tilt angle, the total drag reduction efficiency decreases gradually; the viscous drag reduction efficiency first increases and then decreases, finally tending to be stable; and the total and viscous drag reduction efficiency reaches 20.7% and 26.7%, respectively. The flow field results indicate that the pressure drag mainly originates at the front row of the spines and that the total pressure drag can be effectively controlled by reducing the former pressure drag. With the increase in low-speed fluid and the reduction in the near-wall fluid velocity gradient, the viscous drag can be weakened. Nevertheless, the drag reduction effect is achieved only when the decrement of viscous drag is greater than the increment of pressure drag. This work can serve as a theoretical basis for optimizing the structure and distribution parameters of spines on bionic non-smooth surfaces.

5.
Chem Commun (Camb) ; 57(24): 3018-3021, 2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33624677

RESUMO

Catalytic enantioselective [4+3] cycloaddition reaction between o-quinone methides and oxiranes was achieved by using a chiral N,N'-dioxide/TbIII complex as the catalyst, affording medium-sized hydrodioxepine derivatives in high yields (up to 99%) with good to excellent diastereo-(up to 94 : 6 dr) and enantioselectivities (up to 97% ee). The topographic steric maps and distribution of the buried volume (% VBur) of the catalysts via Cavallo's SambVca 2 tool were collected to effectively represent the chiral pocket of metal complexes of chiral N,N'-dioxides.

6.
Org Lett ; 23(5): 1856-1861, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33621106

RESUMO

The asymmetric catalytic synthesis of 3-cyclotryptamine substituted oxindoles through formal [4 + 2] cycloaddition/cyclization cascade is described. A wide range of cyclotryptamine derivatives were obtained in enantioenriched form under mild reaction conditions and were found to have potential anticancer activity. The strategy enables ready assembly of cyclotryptamine subunits at the C3a-C3a' positions with two quaternary stereogenic centers in cis-selectivity, leading to the concise synthesis of optically active cis-bis(hexahydropyrroloindole) and others of the cyclotryptamine alkaloid family.

7.
Artigo em Inglês | MEDLINE | ID: mdl-33416942

RESUMO

INTRODUCTION: Although recent clinical trials have demonstrated the efficacy of CD19-directed chimeric antigen receptor (CAR) T-cell therapy for refractory or relapsed B acute lymphoblastic leukemia (r/r B-ALL), most trials exclude patients with high-burden CNS leukemia (CNSL) to avoid the risk of severe neurotoxicity. There were only sparse cases describing the effect of CAR T cells on low-burden CNSL, and the safety and effectiveness of CAR T cells in high-burden CNSL remains unknown. METHODS: Here, we retrospectively analyzed the results of CD19 CAR T-cell therapy in 12 pediatric patients that had low (Blasts < 20/µL in CSF) or high-burdens (Blasts or intracranial solid mass) of CNS B-ALL, that are enrolled in three clinical trials and one pilot study at Beijing Boren Hospital RESULTS: Eleven patients (91.7%) achieved complete remission (CR) on day 30, and one patient got CR on day 90 after infusion. Most patient experienced mild cytokine-release syndrome. However, of the five patients who retained > 5/µL blasts in CSF or a solid mass before CAR T-cell expansion, four developed severe (grade 3-4) neurotoxicity featured by persistent cerebral edema and seizure, and they fully recovered after intensive managements. Sustained remission was achieved in 9 of the 12 patients, resulted in a 6-month leukemia-free survival rate of 81.8% (95% CI 59.0-100). Only one patient has CNS relapse again. CONCLUSION: Our study demonstrates that CAR T cells are effective in clearing both low- and high-burden CNSL, but a high CNSL burden before CAR T-cell expansion may cause severe neurotoxicity requiring intense intervention.

8.
J Am Chem Soc ; 143(5): 2394-2402, 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33507075

RESUMO

The homologation of ketones with diazo compounds is a useful strategy to synthesize one-carbon chain-extended acyclic ketones or ring-expanded cyclic ketones. However, the asymmetric homologation of acyclic ketones with α-diazo esters remains a challenge due to the lower reactivity and complicated selectivity. Herein, we report the enantioselective catalytic homologation of acetophenone and related derivatives with α-alkyl α-diazo esters utilizing a chiral scandium(III) N,N'-dioxide as the Lewis acid catalyst. This reaction supplies a highly chemo-, regio-, and enantioselective pathway for the synthesis of optically active ß-keto esters with an all-carbon quaternary center through highly selective alkyl-group migration of the ketones. Moreover, the ring expansion of cyclic ketones was accomplished under slightly modified conditions, affording a series of enantioenriched cyclic ß-keto esters. Density functional theory calculations have been carried out to elucidate the reaction pathway and possible working models that can explain the observed regio- and enantioselectivity.

9.
Biochem Biophys Res Commun ; 534: 149-156, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33309274

RESUMO

Natural killer (NK) cells are pivotal effector lymphocytes characterized for the innate immune response to pathogenic microorganism and tumor cells without priming and sensitization. Despite emerging knowledge has highlighted the rosy prospects in tumor immunosurveillance, yet the large-scale clinical application of NK cell-based therapy is hindered largely attributes to the defects in generating sufficient and high-quality cellular products. Herein, on the basis of 16 kinds of candidate combinations, we investigated the feasibility of cytokine cocktail-based strategy for convenient and standardized NK cell cultivation as well as the multifaceted characteristics and cytotoxicity against tumor cells. Our results revealed that joint utilization of Interleukin (IL)-2, IL-15, IL-18 manifested the optimal facilitation upon the ex vivo expansion and proportion of NK cells in peripheral blood mononuclear cells (PBMCs). Meanwhile, the obtained NK cell population expressed high levels of activating molecules (CD16 and NKG2D) and exhibited splendid cytotoxicity against K562 cell line. Collectively, with the aid of cytokine-based programming, we established an alternative strategy for facilitating the large-scale persistence and activation of NK cells from peripheral blood, which would benefit the NK cell- and chimeric antigen receptor-modified NK (CAR-NK) cell-based autologous or allogeneic tumor immunotherapy.


Assuntos
Citotoxicidade Imunológica , Interleucinas/farmacologia , Células Matadoras Naturais/imunologia , Células Cultivadas , Humanos , Memória Imunológica , Interleucina-15/farmacologia , Interleucina-18/farmacologia , Interleucina-2/farmacologia , Células K562 , Células Matadoras Naturais/efeitos dos fármacos , Leucócitos Mononucleares/imunologia
10.
J Cell Mol Med ; 25(2): 1089-1099, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33314568

RESUMO

Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity are two major CAR T related toxicities. With the interventions of Tocilizumab and steroids, many patients can recover from severe CRS. However, some patients are refractory to steroids and develop life-threatening consequences. Ruxolitinib is an oral JAKs inhibitor and promising drug in inflammatory diseases. In this pilot study, we evaluate the efficacy of Ruxolitinib in CRS. Of 14 r/r B-ALL children who received CD19 or CD22 CAR T cell therapies, 4 patients developed severe (≥grade 3) CRS with symptoms that were not alleviated with high-dose steroids and thus received ruxolitinib. Rapid resolution of CRS symptoms was observed in 4 patients after ruxolitinib treatment. Serum cytokines significantly decreased after ruxolitinib intervention. All patients achieved complete remission on day 30 after infusion, and we could still detect CAR T expansion in vivo despite usage of ruxolitinib. There were no obvious adverse events related to ruxolitinib. In vitro assays revealed that ruxolitinib could dampen CAR T expansion and cytotoxicity, suggesting that the timing and dosage of ruxolitinib should be carefully considered to avoid dampening anti-leukaemia response. Our results suggest that ruxolitinib is active and well tolerated in steroid-refractory and even life-threatening CRS.

11.
Chem Commun (Camb) ; 2020 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-33305782

RESUMO

The chiral amide-guanidine-catalyzed asymmetric formal [3+2] cycloaddition of isatogens with azlactones is presented. This strategy provided a facile and feasible route to chiral indolin-3-one derivatives bearing two contiguous tetrasubstituted stereocenters in moderate to good yields with high diastereoselectivities and enantioselectivities. A possible working mode was proposed to elucidate the chiral control of the process.

12.
Artigo em Inglês | MEDLINE | ID: mdl-33196141

RESUMO

Due to the synergistic "push-pull" effect of vicinal electron-donating and electron-withdrawing groups, donor-acceptor (D-A) cyclopropanes have been recognized as one of the most powerful reagents to generate polyfunctional reactive intermediates after a strain-driven ring cleavage. Enantioselective reactions of D-A cyclopropanes provide an efficient approach to enantioenriched acyclic and cyclic compouds. A number of chiral Lewis/Brønsted acids, transition metals and organocatalysts have been designed for such transformations, including ring-openings, annulations and rearrangements. This Minireview highlights the developments and new advances in this field and familiarizes the Reader with new synthetic opportunities offered by these interesting methodologies.

13.
Chem Commun (Camb) ; 56(87): 13429-13432, 2020 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-33043926

RESUMO

Utilizing the C4 reactive site of cyclopropyl ketones and a chiral N,N'-dioxide-scandium(iii) complex as a catalyst, a concise ring-opening/cyclization/thio-Michael cascade method was developed for the synthesis of chiral benzothiazole derivatives from a simple 2-aminothiophenol material. The kinetic resolution and the origin of stereoselectivity were elucidated via a possible catalytic model.

14.
Sci Total Environ ; : 143141, 2020 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-33121766

RESUMO

In response to the potential water conflict caused by climate change and increased population, an integrated water yield analysis from the perspective of the coupled human-natural system is clearly required. This paper conducted an integrated water yield analysis in the Yellow River basin (YRB), China, with applications for irrigated cropland water modeling and many field, statistical and satellite images. We found the following during 2000-2017: (1) The irrigation water consumption, rain-fed water consumption of cropland and rain-fed water consumption of natural ecosystems all increased significantly. (2) Ecological restoration caused a consequence of the 81.7 108 m3 water consumption transfer from cropland to natural ecosystems. (3) Water consumption variability was strongly related to irrigation expansion and ecological restoration, and this variability dominated the high water yield variability in the midstream YRB (95.73% ± 0.5%). (4) The increased downstream human water use stress was mainly affected by increased downstream water use and upstream water yield change, with contribution ratios of 1.67 and -0.72, respectively. The study declares the intense relationship between ecological restoration, crop production and socioeconomic activities within the water-limited river basin. This research also highlights that synthetic river basin management is essential to balance the water demand between different sectors and between the upper stream and downstream sections of a basin.

15.
Org Lett ; 22(21): 8708-8713, 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33074003

RESUMO

A unique chiral amine organocatalyst with a bispidine structure was found to be efficient for the diastereo- and enantioselective Mannich reaction of isatin ketimines with ketones. A series of 3-substituted 3-amino-2-oxindoles bearing vicinal tertiary and quaternary chiral stereogenic centers were obtained in excellent yields with excellent dr and ee values. The gram-scale synthesis and transformation of the product showed the practicability of this methodology. In addition, a possible transition state model was proposed to explain the origin of the stereoselectivity.

16.
Chem Commun (Camb) ; 56(84): 12757-12760, 2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-32966405

RESUMO

A highly efficient enantioselective dicarbofunctionalization reaction of (E)-alkenyloxindoles with pyridinium salts was realized. The process includes the chiral N,N'-dioxide-Sc(iii) complex-catalyzed regio-, diastereo-, and enantioselective [3+2] cycloaddition reaction and the following photo-promoted aza-Norrish II type rearrangement. A series of 2-pyridyl substituted oxindole derivatives were obtained in good yields with moderate to good diastereo- and enantioselectivities.

17.
J Am Chem Soc ; 142(37): 15975-15985, 2020 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-32816475

RESUMO

Enantioselective diverse synthesis of a small-molecule collection with structural and functional similarities or differences in an efficient manner is an appealing but formidable challenge. Asymmetric preparation and branching transformations of tetrahydroindolizines in succession present a useful approach to the construction of N-heterocycle-containing scaffolds with functional group, and stereochemical diversity. Herein, we report a breakthrough toward this end via an initial diastereo- and enantioselective [3 + 2] cycloaddition between pyridinium ylides and enones, following diversified sequential transformations. Chiral N,N'-dioxide-earth metal complexes enable the generation of optically active tetrahydroindolizines in situ, across the strong background reaction for racemate-formation. In connection with deliberate sequential transformations, involving convenient rearomatic oxidation, and light-active aza-Norrish II rearrangement, the tetrahydroindolizine intermediates were converted into the final library including 3-arylindolizine derivatives and dicarbofunctionalized 1,5-dicarbonyl compounds. More importantly, the stereochemistry of four-stereogenic centered tetrahydroindolizine intermediates could be efficiently transferred into axial chirality in 3-arylindolizines and vicinal pyridyl and aryl substituted 1,5-diketones. In addition, densely functionalized cyclopropanes and bridged cyclic compounds were also discovered depending on the nature of the pyridinium ylides. Mechanism studies were involved to explain the stereochemistry during the reaction processes.

18.
Org Lett ; 22(17): 6744-6749, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32818380

RESUMO

An enantioselective three-component reaction of diazoacetates, 2-oxo-3-ynoates, and nitrosoarenes has been developed by using a chiral N,N'-dioxide/Ni(OTf)2 complex. This catalytic manifold allows rapid access to a series of multifunctional chiral epoxides containing an imino ketone substituent in moderate to good yields (up to 82%) and excellent diastereo- and enantioselectivities (up to >95/5 dr and 99% ee) with high levels of Z/E ratios (up to >95/5 Z/E) under mild reaction conditions.

19.
Nat Commun ; 11(1): 3869, 2020 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-32747706

RESUMO

The investigation of diverse reactivity of ß,γ-unsaturated carbonyl compounds is of great value in asymmetric catalytic synthesis. Numerous enantioselective transformations have been well developed with ß,γ-unsaturated carbonyl compounds as nucleophiles, however, few example were realized by utilizing them as not only nucleophiles but also electrophiles under a same catalytic system. Here we report a regioselective catalytic asymmetric tandem isomerization/α-Michael addition of ß,γ-unsaturated 2-acyl imidazoles in the presence of chiral N,N'-dioxide metal complexes, delivering a broad range of optically pure 1,5-dicarbonyl compounds with two vicinal tertiary carbon stereocenters in up to >99% ee under mild conditions. Meanwhile, stereodivergent synthesis is disclosed to yield all four stereoisomers of products. Control experiments suggest an isomerization process involved in the reaction and give an insight into the role of NEt3. In addition, Mannich reaction and sulfur-Michael addition of ß,γ-unsaturated 2-acyl imidazoles proceed smoothly as well under the same catalytic system.

20.
Chem Commun (Camb) ; 56(69): 10002-10005, 2020 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-32725013

RESUMO

A nickel(ii) catalyzed enantioselective thio-Claisen rearrangement of α-diazo pyrazoleamides with thioindoles was realized with modified chiral N,N'-dioxide ligands, affording a variety of C3-substituted indole derivatives in high yields (up to 95%) with excellent enantioselectivities (up to 96% ee) under mild reaction conditions. A possible transition state model was proposed based on previous reports and the X-ray crystal structure of the catalyst.

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