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1.
J Org Chem ; 85(5): 3676-3688, 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-31977213

RESUMO

The present work focuses on a theoretical investigation of the plausible mechanism, determination of catalytically active species, and understanding of the regioselectivity in the InCl3-catalyzed cycloaddition of N-tosyl formaldimine with alkenes or allenes. InCl3 and InCl2+ coordinated by dichloroethane (InCl2+-DCE) were investigated as model catalytic systems. DFT data supported that InCl2+-DCE represent the plausible in situ generated catalytic species. The catalytic cycle starts from the coordination of N-tosyl formaldimine to InCl2+-DCE, generating an In-complexed iminium intermediate. This then undergoes intermolecular reaction (aza-Prins) with alkene substrate to form a carbocation intermediate, which is chemoselectively attacked by the second N-tosyl formaldimine molecule to form a formaldiminium intermediate. In a final step, this intermediate undergoes the ring closure, leading to hexahydropyrimidine along with the regeneration of catalyst. In addition, our DFT results indicate that N-tosyl formaldimine not only acts as a reactant but also accelerates the 1,3-H-shift as a proton acceptor, giving an experimentally observed allylamide product. Also, the "iminium/alkene/imine" path was supported by calculation results for diastereoselective [2 + 2 + 2] reaction using an internal alkene. Finally, the regioselectivity of the InCl3-catalyzed cycloaddition using allenes along with N-tosyl formaldimine was also analyzed.

2.
Angew Chem Int Ed Engl ; 59(10): 3966-3970, 2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-31898399

RESUMO

The first total synthesis of the Euphorbia diterpenoid pepluanol B in both racemic and enantioenriched form involves 20 steps from a known bicyclic diol. This synthesis features an unprecedented bromo-epoxidation to control the eight-membered-ring conformation. In addition, salient reactions for the construction of the tetracyclic backbone include a sterically challenging aldol reaction to establish the quaternary center, a ring closing metathesis (RCM) to forge the eight-membered ring, and a diastereoselective cyclopropanation to assemble the embedded cyclopropane motif.

3.
Nature ; 577(7788): 109-114, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31827280

RESUMO

Activation of RIPK1 controls TNF-mediated apoptosis, necroptosis and inflammatory pathways1. Cleavage of human and mouse RIPK1 after residues D324 and D325, respectively, by caspase-8 separates the RIPK1 kinase domain from the intermediate and death domains. The D325A mutation in mouse RIPK1 leads to embryonic lethality during mouse development2,3. However, the functional importance of blocking caspase-8-mediated cleavage of RIPK1 on RIPK1 activation in humans is unknown. Here we identify two families with variants in RIPK1 (D324V and D324H) that lead to distinct symptoms of recurrent fevers and lymphadenopathy in an autosomal-dominant manner. Impaired cleavage of RIPK1 D324 variants by caspase-8 sensitized patients' peripheral blood mononuclear cells to RIPK1 activation, apoptosis and necroptosis induced by TNF. The patients showed strong RIPK1-dependent activation of inflammatory signalling pathways and overproduction of inflammatory cytokines and chemokines compared with unaffected controls. Furthermore, we show that expression of the RIPK1 mutants D325V or D325H in mouse embryonic fibroblasts confers not only increased sensitivity to RIPK1 activation-mediated apoptosis and necroptosis, but also induction of pro-inflammatory cytokines such as IL-6 and TNF. By contrast, patient-derived fibroblasts showed reduced expression of RIPK1 and downregulated production of reactive oxygen species, resulting in resistance to necroptosis and ferroptosis. Together, these data suggest that human non-cleavable RIPK1 variants promote activation of RIPK1, and lead to an autoinflammatory disease characterized by hypersensitivity to apoptosis and necroptosis and increased inflammatory response in peripheral blood mononuclear cells, as well as a compensatory mechanism to protect against several pro-death stimuli in fibroblasts.

4.
Chemistry ; 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31830333

RESUMO

Palladium-catalyzed asymmetric [4+5] annulation of ortho -quinone methides ( o -QMs) with substituted vinylethylene carbonates (VECs) is described for the first time, giving a novel enantioselective approach to chiral 9-membered benzoheterocycles. Based on this designed [4+5] annulation, an unprecedented silica gel-promoted tandem rearrangement reaction featuring a unique asymmetric aromatic Claisen rearrangement is explored at room temperature, offering a new method for asymmetric construction of all-carbon quaternary stereocenter embedded in chiral functionalized homoallylic alcohols.

5.
Yi Chuan ; 41(11): 994-1008, 2019 Nov 20.
Artigo em Chinês | MEDLINE | ID: mdl-31735703

RESUMO

Deafness has become one of the most frequent health problems worldwide, and affects almost every age group. Hair cell damage or absence is the main cause of hearing loss, but there is no successful treatment to heal deafness. MicroRNA (miRNA), as a highly conserved endogenous non-coding small RNA, plays an important role in inner ear cochlea and hair cell development. In this review, we elaborate on the expression and function of miRNAs in cochlear hair cell development, and reveal its indispensable important role. We summarize the molecular mechanism of miRNA in regulating transcription factors involved in cochlear hair cell development, which may provide references and insights for hair cell regeneration in vivo and cellular transplantation therapy of deafness.


Assuntos
Células Ciliadas Auditivas/fisiologia , MicroRNAs/genética , Cóclea/crescimento & desenvolvimento , Orelha Interna/crescimento & desenvolvimento , Humanos , Neurogênese
6.
Org Lett ; 21(13): 5219-5224, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31247740

RESUMO

A variety of axially chiral biaryldiols were synthesized in good yields with excellent atropo-enantioselectivities through construction of axially chiral indoles catalyzed by asymmetric hydrogen-bond donors. In addition, the new axially chiral compounds were proved to be efficient and practical catalysts for asymmetric catalysis. The strategy not only provides a novel method to synthesize axially chiral compounds but also extends the scope of chiral catalysts.

7.
Org Lett ; 21(9): 3131-3135, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-31013104

RESUMO

A cyclization of propargylic alcohols with tert-butyl nitrite at room temperature in air was achieved using Pd(OAc)2 as catalyst. The first reported 4-oxoisoxazoline N-oxides could be directly accessed from a range of multisubstituted propargylic alcohols in moderate to excellent yields under mild conditions. Density functional theory calculations indicated that the reaction proceeds through a palladium-catalyzed NO2 addition that efficiently generates a ketoxime radical, which eventually produces 4-oxoisoxazoline N-oxide.

8.
Artigo em Inglês | MEDLINE | ID: mdl-30594853

RESUMO

It is found that hypobromous acid (HOBr) can affect the activity of type IV collagen. Herein, we synthesized a lysosome-targeted fluorescence probe NA-lyso based on Suzuki coupling reaction with naphthalimide as a fluorescent group. HOBr can oxidize the amino group and methylthio group, which increased the degree of conjugation of the probe, thereby affecting its optical properties. Accordingly, it can establish a method for the specific detection of HOBr. NA-lyso has the properties including fast response, high fluorescence quantum yield (Φ = 59.17%), high selectivity, low cytotoxicity and good membrane-permeability. The probe can locate to lysosome of cells. The potential of the probe as biosensor for HOBr was demonstrated by imaging of exogenous and endogenous HOBr in living cells and in mice. In consequence, NA-lyso is expected to be a powerful tool to detect HOBr in complex biosystem and provides a means of exploring physiological functions associated with HOBr in living organisms.


Assuntos
Bromatos/análise , Corantes Fluorescentes/química , Lisossomos/metabolismo , Animais , Feminino , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Luminescência , Camundongos , Sondas Moleculares/química , Espectrometria de Fluorescência , Espectrofotometria Ultravioleta , Fatores de Tempo
9.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 47(3): 320-326, 2018 May 25.
Artigo em Chinês | MEDLINE | ID: mdl-30226336

RESUMO

Exosome is a specific subset of vesicles from intracellular origin vesicles containing varies of microRNAs, mRNAs, proteins and lipids. It has been demonstrated that contents of exosomes could be altered due to different physiological and pathological stress, which could be used as clinical biomarker to reveal the disease state. In addition, according to previous studies, exosomes could exert protective roles for cardiovascular diseases such as atherosclerosis, myocardial infarction and ischemia/reperfusion injury, etc. The aim of this review is to summarize current research progress on exosomes, related implications in diagnosis and treatment of cardiovascular diseases and corresponding mechanisms.


Assuntos
Doenças Cardiovasculares , Exossomos , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/terapia , Humanos , MicroRNAs/metabolismo , Pesquisa/tendências
10.
Chemistry ; 24(71): 18863-18867, 2018 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-30199120

RESUMO

Here a highly efficient cascade approach is reported that combines a cycloaddition reaction with a regioselective strain-release process to afford diverse heterocyclic frameworks through bifunctional catalysis. The cooperation of hydrogen-bonding network activation and a regiodivergent strain-assisted effect is the key to promoting this complex chemical transformation, leading to the generation of two different ring systems in high yields with excellent stereoselectivities. The reaction proceeded by a mechanism involving a "spring-loaded" intermediate with switchable C-C bond cleavages achieved by controllable ring-strain release. This reaction was also amenable to gram scale synthesis with only 0.1 mol % catalyst loading.

11.
ACS Appl Mater Interfaces ; 10(28): 23976-23986, 2018 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-29920195

RESUMO

A new series of five three-dimensional Ln(III) metal-organic frameworks (MOFs) formulated as [Ln4(µ6-L)2(µ-HCOO)(µ3-OH)3(µ3-O)(DMF)2(H2O)4] n {Ln3+ = Tb3+ (1), Eu3+ (2), Gd3+ (3), Dy3+ (4), and Er3+ (5)} was successfully obtained via a solvothermal reaction between the corresponding lanthanide(III) nitrates and 2-(6-carboxypyridin-3-yl)terephthalic acid (H3L). All of the obtained compounds were fully characterized, and their structures were established by single-crystal X-ray diffraction. All products are isostructural and possess porous 3D networks of the fluorite topological type, which are driven by the cubane-like [Ln4(µ3-OH)3(µ3-O)(µ-HCOO)]6+ blocks and µ6-L3- spacers. Luminescent and sensing properties of 1-5 were investigated in detail, revealing a unique capability of Tb-MOF (1) for sensing acetone and metal(III) cations (Fe3+ or Ce3+) with high efficiency and selectivity. Apart from a facile recyclability after sensing experiments, the obtained Tb-MOF material features a remarkable stability in a diversity of environments such as common solvents, aqueous solutions of metal ions, and solutions with a broad pH range from 4 to 11. In addition, compound 1 represents a very rare example of the versatile Ln-MOF probe capable of sensing Ce3+ or Fe3+ cations or acetone molecules.

12.
Dalton Trans ; 47(2): 465-474, 2018 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-29226925

RESUMO

A trifunctional aromatic building block (H2L) containing three different types of functional groups (carboxyl C([double bond, length as m-dash]O)OH, aldehyde C([double bond, length as m-dash]O)H, and O-ether) was applied for the hydrothermal synthesis of two novel lanthanide 2D coordination polymers [Ln(µ-HL)(µ3-L)(phen)]n {Ln = Tb (1) and Eu (2); H2L = 5-methoxy-(4-benzaldehyde)-1,3-benzene dicarboxylic acid; phen = 1,10-phenanthroline}. Both compounds 1 and 2 are isostructural and reveal very complicated 2D metal-organic double layers with the 3,4L27 topology. The presence of free aldehyde groups positioned outside of the double layers opens up a possibility of using them as functional groups toward sensing amines and small organic molecules. The fluorescence measurements for the Tb derivative 1 reveal that it acts as an efficient fluorescence sensor for p-phenylenediamine, benzidine and acetone molecules via a luminescence quenching effect. A similar sensing behavior was observed for the Eu compound 2. Moreover, thin-films of 1-PEG on glass (1-PEG-glass thin-film material) were fabricated and investigated for the detection of amine vapors.

13.
ACS Omega ; 3(8): 9339-9347, 2018 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-31459067

RESUMO

A detailed theoretical analysis of the mechanism and chemoselectivity for gold(I)-catalyzed reaction of o-(alkynyl)styrene containing an isopropyl and a methyl at the terminal position of the alkene has been reported in this work. Two different counterions (SbF6 - and OTs-) were studied as model catalysts. According to our calculation, for SbF6 -, the reaction pathway is more prone to direct 1,2-H shifts (isopropyl H) than the elimination and ring expansion pathway. However, an elimination pathway affords the indenyl derivative by forming p-toluenesulfonic acid (HOTs), which may be the main pathway in the presence of OTs-. The chemoselectivity for the title reaction is mainly determined by the electronic effect of the counterion and the substituent rather than the steric effect. In other words, less basic SbF6 - mainly provides the charge separation effect rather than assisted proton elimination. However, the more basic OTs- mainly assist proton elimination through the formation of HOTs. In addition to the good agreement with the experimental data, the density functional theory results also provide a significant contribution to the understanding of the reaction mechanism.

14.
Yi Chuan ; 39(10): 897-907, 2017 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-29070485

RESUMO

Wnt signaling pathway plays important roles in the development and homeostasis of multicellular organisms. Through their bindings with the Frizzled receptors, the Wnt ligands regulate a wide range of developmental processes, such as axis patterning, cell division, and cell fate specification. Wnt signaling plays vital roles in the development of inner ear of the mouse. In the early stages of inner ear development, Wnt signaling specifies the size of the placode and the formation of the otic vesicle. In later stages, Wnt signaling mediates hair cell specification and orients the stereociliary bundles in a uniform direction. In this review, we summarize the current knowledge on the roles of Wnt signaling in hair cell differentiation and regeneration, which may provide references and insights for investigators in the field.


Assuntos
Células Ciliadas Auditivas/citologia , Regeneração , Via de Sinalização Wnt/fisiologia , Animais , Diferenciação Celular , Células Ciliadas Auditivas/fisiologia , Humanos , Trombospondinas/fisiologia
15.
Dalton Trans ; 45(46): 18610-18621, 2016 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-27827497

RESUMO

Three novel 2D coordination polymers [Tb2(µ4-L)2(µ-HL)(µ-HCOO)(DEF)]n (Tb-L), [Eu(µ4-L)(L)(H2O)2]n (Eu-L), and [Nd(µ4-L)(L)(H2O)2]n (Nd-L) were assembled from the corresponding lanthanide(iii) nitrates and 5 methoxy-(4-benzaldehyde)-1,3-benzenedicarboxylic acid (H2L) as a main multifunctional building block bearing carboxylate and aldehyde functional groups, using H2O/DEF {DEF = N,N-diethylformamide} as a reaction medium. The obtained coordination polymers were isolated as stable microcrystalline solids and fully characterized by elemental analysis, FT-IR spectroscopy, TGA, BET, PXRD, and single-crystal X-ray diffraction methods. Their structures feature intricate 2D metal-organic networks, which were topologically classified as underlying layers with the 4,6L26 (for Tb-L) or sql (for Eu-L and Nd-L) topologies. Besides, a novel series of mesoporous hybrid materials wherein the Tb-L, Eu-L, or Nd-L coordination polymers are covalently grafted into the amine-functionalized SBA-15-NH2 or MCM-41-NH2 matrices (via the formation of Schiff-base groups) was also synthesized and fully characterized. These hybrid materials show high thermal and photoluminescence stability, as well as remarkable chemical resistance to boiling water, and acidic or alkaline medium. Luminescent properties of the parent coordination polymers and derived hybrid materials are investigated in detail, showing that the latter combine the luminescent characteristics (intense green or red emissions and excellent stability) of lanthanide coordination polymers and structural features of ordered mesoporous silica molecular sieves. Moreover, light emitting devices were assembled, by coating the hybrid materials onto the surface of UV-LED bulbs, and showed excellent light emitting properties.

16.
Acta Pharmacol Sin ; 37(6): 845-56, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27133297

RESUMO

AIM: Dexamethasone (DEX) is a widely used synthetic glucocorticoid, which has shown anti-cancer efficacy and anti-estrogenic activity. In this study we explored the possibility that DEX might be used as an endocrine therapeutic agent to treat human non-small cell lung cancer (NSCLC). METHODS: The viability and proliferation of human NSCLC cell lines A549 and H1299 were assessed in vitro. Anti-tumor action was also evaluated in A549 xenograft nude mice treated with DEX (2 or 4 mg·kg(-1)·d(-1), ig) or the positive control tamoxifen (50 mg·kg(-1)·d(-1), ig) for 32 d. The expression of estrogen sulfotransferase (EST) in tumor cells and tissues was examined. The intratumoral estrogen levels and uterine estrogen responses were measured. RESULTS: DEX displayed mild cytotoxicity to the NSCLC cells (IC50 >500 µmol/L) compared to tamoxifen (IC50 <50 µmol/L), but it was able to inhibit the cell proliferation at low micromolar ranges. Furthermore, DEX (0.1-10 µmol/L) dose-dependently up-regulated EST expression in the cells, and inhibited the cell migration in vitro. Triclosan, a sulfation inhibitor, was able to diminish DEX-caused inhibition on the cell viability. In A549 xenograft nude mice, DEX or tamoxifen administration remarkably suppressed the tumor growth. Moreover, DEX administration dose-dependently increased EST expression in tumor tissues, and reduced intratumoral estrogen levels as well as the volumes and weights of uterine. CONCLUSION: DEX suppresses the growth of A549 xenograft tumors via inducing EST and decreasing estradiol levels in tumor tissues, suggesting that DEX may be used as anti-estrogenic agent for the treatment of NSCLC.


Assuntos
Antineoplásicos Hormonais/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Dexametasona/farmacologia , Antagonistas de Estrogênios/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Pulmão/efeitos dos fármacos , Sulfotransferases/metabolismo , Células A549 , Animais , Antineoplásicos Hormonais/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dexametasona/uso terapêutico , Antagonistas de Estrogênios/uso terapêutico , Estrogênios/metabolismo , Feminino , Humanos , Pulmão/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos Nus , Sulfotransferases/análise
17.
J Mol Model ; 22(1): 16, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26696541

RESUMO

A theoretical study of the N-heterocyclic carbene (NHC)-catalyzed cyclotetramerization of acrylates forming trisubstituted cyclopentenones indicates a mechanism through a key deoxy-Breslow intermediate generated from one molecule of NHC and two molecules of methyl acrylate (MA). Pathways involving different proton-transfer (α or ß) and the role of a tert-butoxide ( (t) BuO(-)) group were investigated.

18.
Artigo em Inglês | MEDLINE | ID: mdl-26232579

RESUMO

Two Schiff-base fluorescent sensors have been synthesized, which both can act as fluorescent probes for Al(3+), upon addition of Al(3+), they exhibit a large fluorescence enhancement which might be attributed to the formation of 1:1 ligand-Al complexes which inhibit photoinduced electron transfer (PET) progress, and that the proposed binding modes of the sensors and Al(3+) are identified by theoretical calculations.


Assuntos
Alumínio/análise , Corantes Fluorescentes/química , Bases de Schiff/química , Cátions/análise , Transporte de Elétrons , Fluorescência , Ligantes , Modelos Moleculares , Espectrometria de Fluorescência
19.
Chem Asian J ; 10(2): 422-6, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25363167

RESUMO

A new chemodosimeter for the highly selective sensing and imaging of biothiols was designed and realized in phosphate-buffered saline solution at pH 7.4 through a fluorescence "off-on" response. A unique mechanism featuring a two-step cascade (biothiols→H2 O) sequence for this remarkable recognition is disclosed for the first time.


Assuntos
Cumarínicos/química , Corantes Fluorescentes/química , Compostos de Sulfidrila/química , Sulfonamidas/química , Cristalografia por Raios X , Cisteína/química , Corantes Fluorescentes/síntese química , Glutationa/química , Células HeLa , Humanos , Microscopia de Fluorescência , Conformação Molecular , Teoria Quântica , Espectrometria de Fluorescência , Sulfonamidas/síntese química
20.
Org Biomol Chem ; 12(42): 8433-41, 2014 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-25224932

RESUMO

We report here the theoretical analysis of the mechanism and regioselectivity of gold(I) or platinum(II) catalyzed intramolecular hydroarylation to pyrrolopyridinones and pyrroloazepinones. AuPH3(+) and PtCl2 have been considered to account for some experimental observations. Our calculation results indicate that in the case of cationic gold the nucleophilic attack of the pyrrole on the activated alkyne occurs in an exo-dig fashion generating a six-membered intermediate, which upon deprotonation and protodeauration forms pyrrolopyridinone. When platinum is used, an endo-dig fashion is observed generating a seven-membered intermediate. After deprotonation and protodeplatination pyrroloazepinone is formed. Whether for exo-dig (gold(I)) or endo-dig (platinum(II)) cyclization, a [1,2]-migration would not be needed.

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