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1.
Eur J Med Chem ; 192: 112172, 2020 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-32163815

RESUMO

Discovery of novel anti-obesity agents is a challenging and promising research area. Based on our previous works, we synthesized 40 novel ß-indoloquinazoline analogues by altering the skeleton and introducing preferential side chains, evaluated their lipid-lowering activity and summarized the structure-activity relationships. In combination with an evaluation of the lipid-lowering efficacies, AMP-dependent activated protein kinase (AMPK) activating ability and liver microsomal stability, compound 23 (named as IQZ23) was selected for further studies. IQZ23 exerted a high efficacy in decreasing the triglyceride level (EC50 = 0.033 µM) in 3T3-L1 adipocytes. Mechanistic studies revealed the lipid-lowering activity of IQZ23 was dependent on the AMPK pathway by modulating ATP synthase activity. This activation was accompanied by mitochondrial biogenesis and oxidation capacity increased, and insulin sensitivity enhanced in pertinent cell models by various interventions. Correspondingly, IQZ23 (20 mg/kg, i.p.) treatment significantly reversed high fat and cholesterol diet (HFC)- induced body weight increases and accompanying clinical symptoms of obesity in mice but without indicative toxicity. These results indicate that IQZ23 could be a useful candidate for the treatment of obesity and related metabolic disorders.

2.
Chem Commun (Camb) ; 56(1): 82-85, 2020 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-31790113

RESUMO

The iodofluorination of alkynyl and alkenyl MIDA (N-methyliminodiacetyl) boronates led to the synthesis of two types of fluorinated organoborons bearing a valuable C-I bond. The B(MIDA) moiety confers exclusive regioselectivity to the reaction, and the products were formed in generally good yields. Preliminary utility of the products was demonstrated.

3.
J Org Chem ; 84(21): 13232-13241, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31565939

RESUMO

Analogues of cancer-associated Lewis Y (Ley) antigen with varying structures at the reducing end were synthesized by a highly efficient strategy involving one-pot preactivation-based iterative glycosylation to obtain the key tetra-/pentasaccharide intermediates, which was followed by stereoselective fucosylation. After global deprotection, these oligosaccharides were coupled with carrier protein keyhole limpet hemocyanin. The resultant glycan-protein conjugates were subjected to immunological studies in mice. It was disclosed that the conjugate of the pentasaccharide analogue of Lewis Y antigen was more immunogenic than that of the hexasaccharide analogue, but the antisera of both conjugates could indiscriminately recognize each carbohydrate hapten. These results suggested that the short Lewis Y analogue may be utilized to develop functional conjugate cancer vaccines. More importantly, the results also proved that the reducing-end glucose residue in the hexasaccharide analogue of Lewis Y was probably not involved in its interaction with the immune system, whose discovery can have a broad impact on the design of new cancer vaccines.

4.
J Org Chem ; 84(20): 12966-12974, 2019 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-31490696

RESUMO

An oxidative [3 + 2] C-H spiroannulation reaction of 2-alkenylphenols with ynamides has been developed toward the synthesis of spiro[4,5]decane derivatives. This dearomative reaction employs earth-abundant cobalt as the metal catalyst and occurs under rather mild reaction conditions (room temperature). The use of ynamides confers unique reactivity and exclusive regioselectivity. The products bearing an all-carbon quaternary stereogenic center were constructed in generally good yields with good functional group tolerance being observed. Experimental mechanistic studies were conducted, and a possible reaction mechanism is proposed.

5.
Brain Res ; 1724: 146407, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31465773

RESUMO

Normal aging is a risk factor for metabolic disorders such as diabetes, and diabetes is also a recognized cause of accelerated aging. Being able to distinguish changes caused by normal aging from those caused by diabetes, would provide insight into how the aging brain interacts with diabetes. Eight types of MRI metric maps (magnetization relaxation time constants of T1 and T2, cerebral blood flow, cerebrovascular permeability, mean diffusivity, diffusion fractional anisotropy, mean diffusion kurtosis and diffusion directional entropy) were generated for all rats from the three groups of normal young, healthy and 1.5-month diabetic middle-aged rats under investigation. Measurements of multiple MRI indices of cerebral white and gray matter from animals of the three groups provide complementary results and insight into differences between healthy and diabetic white / gray matter in the mid-aged rats. Our data indicate that MRI may distinguish between the normal and diabetes in mid-aged rat brains by measuring either T1 and T2 of gray matter, or fractional anisotropy of white matter and gray matter. Therefore, MRI can distinguish changes of cerebral tissue due to the normal aging from diabetic aging, which may lead to be able to better understand how diabetes accelerates aging in normal brain.

6.
Angew Chem Int Ed Engl ; 58(39): 13784-13788, 2019 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-31347254

RESUMO

The ring-opening reactions of N-methyliminodiacetyl (MIDA) α-chloroepoxyboronates with different nucleophiles allow the modular synthesis of a diverse array of organoboronates. These include seven types of α-functionalized acylboronates and seven types of borylated heteroarenes, some of which are difficult-to-access products using alternative methods. The common synthons, α-chloroepoxyboronates, could be viably synthesized by a two-step procedure from the corresponding alkenyl MIDA boronates. Mild reaction conditions, good functional-group tolerance, and generally good efficiency were observed. The utility of the products was also demonstrated.

7.
Org Lett ; 21(11): 4255-4258, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31095399

RESUMO

A practical synthesis of α-fluorinated imides via the catalyst-free fluorohydroxylation of ynamides is developed. The reaction employs commercially available Selectfluor (F-TEDA-BF4) and H2O as the fluorine and hydroxyl sources, respectively. A broad range of aryl- or alkyl-substituted ynamides were well applicable to the reaction with good functional group tolerance under simple and mild reaction conditions. The synthetic utility of the α-fluoroimide products was demonstrated by several value-added transformations. Preliminary mechanistic studies were conducted.

8.
Brain Res ; 1717: 127-135, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31009610

RESUMO

Diffuse white matter (WM) response to traumatic brain injury (TBI) and transplantation of human bone marrow stromal cells (hMSCs) after the injury were non-invasively and dynamically investigated. Male Wistar rats (300-350 g) subjected to TBI were intravenously injected with 1 ml of saline (n = 10) or with hMSCs in suspension (∼3 × 106 hMSCs, n = 10) 1-week post-TBI. MRI measurements of T2-weighted imaging and diffusional kurtosis imaging (DKI) were acquired on all animals at multiple time points up to 3-months post-injury. Functional outcome was assessed using the Morris water maze test. DKI-derived metrics of fractional anisotropy (FA), axonal water fraction (AWF) and radial kurtosis (RK) longitudinally reveal an evolving pattern of structural alteration post-TBI occurring in the brain region remote from primary impact site. The progressive structural change is characterized by gradual disruption of WM integrity at an early stage (weeks post-TBI), followed by spontaneous recovery at a later stage (months post-TBI). Transplantation of hMSCs post-TBI promotes this structural plasticity as indicated by significantly increased FA and AWF in conjunction with substantially elevated RK at the later stage. Our long-term imaging data demonstrate that hMSC therapy leads to modified temporal profiles of these metrics, inducing an earlier presence of enhanced structural remodeling, which may contribute to improved functional recovery.

9.
Org Lett ; 21(9): 3123-3126, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-30977373

RESUMO

A regio- and stereoselective synthesis of fluorinated 1,4-enynes bearing an all-carbon quaternary center at the propargylic position is developed. The synthesis starts from readily available allenoates and gem-difluoroalkenes and proceeds via a key alkynylenolate intermediate following a nucleophilic addition/ß-F elimination. This reaction occurs under mild reaction conditions with good tolerance to a variety of functional groups. Synthetic utility is demonstrated by further transformations of the products. Furthermore, the reaction can also be applied for the synthesis of α-alkenyl allenoates by using 3,3-disubstituted allenoates.

10.
Nanomaterials (Basel) ; 9(3)2019 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-30862000

RESUMO

Volatile programmable metallization cell is a promising threshold switching selector with excellent characteristics and simple structures. However, the large variation of threshold voltage is a major problem for practical application. In this work, we propose a dual-layer structure to increase selectivity and improve the threshold voltage variation. Compared to single-layer devices, this dual-layer device exhibits higher selectivity (>107) and better threshold voltage uniformity with less than 5% fluctuation during 200 DC switching. The improvement is attributed to good control on the location of the filament formation and rupture after introducing a HfO2 layer. It is deduced that a major factor consists of the difference of Ag ions mobility between SiTe and HfO2 due to the grain boundary quantity.

11.
Chemistry ; 25(16): 4058-4061, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30697832

RESUMO

An efficient synthesis of highly functionalized cyclohexadienylborons via an inverse electron-demand Diels-Alder reaction/CO2 extrusion of alkenyl MIDA boronates with 2-pyrones is outlined. By controlling the reaction temperature, the corresponding C(sp3 )-rich bicyclolactones could also be readily formed. The exo-selective reactions feature good functional-group tolerance, broad substrate scope, and excellent regio- and diastereoselectivity. Oxidation of the cyclohexadienylborons in a one-pot procedure led to the construction of aromatic boronates bearing valuable functional groups. Synthetic transformations of the C-B bond were demonstrated.

12.
Neuroimage ; 188: 616-627, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30578928

RESUMO

The glymphatic system is functional waste clearance path from the brain parenchyma through dynamic exchange of cerebrospinal fluid (CSF) with interstitial fluid (ISF). Impairment of glymphatic waste clearance is involved in the development of neurodegenerative conditions. Despite many recent studies investigating the glymphatic system, few studies have tried to use a mathematical model to describe this system, quantitatively. In this study, we aim to model the glymphatic system from the kinetics of Gd-DTPA tracer measured using MRI in order to: 1) map the glymphatic system path, 2) derive kinetic parameters of the glymphatic system, and 3) provide quantitative maps of the structure and function of this system. In the proposed model, the brain is clustered to similar regions with respect to the profile of contrast agent (CA) density measured by MRI. Then, each region is described as a two-compartment kinetic model 'derived from' or 'clears to' its neighbors with local input function. We thus fit our model to the local cerebral regions rather than to the averaged time signal curve (TSC) of the whole brain. The estimated parameters showed distinctive differences between diabetes mellitus (DM) and control rats. The results suggest that in a typical DM brain the CSF bulk speed in the para-vasculature network is low. In addition, the resulting maps indicate that there may be increased binding and decreased absorbing of large molecules in a diabetic compared with a non-diabetic brain. The important contribution of this work was to fit the model to the local regions rather than to the averaged time signal curve (TSC) of the whole brain. This enabled us to derive quantitative maps of the glymphatic system from MRI.


Assuntos
Diabetes Mellitus/diagnóstico por imagem , Sistema Glinfático/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Modelos Teóricos , Neuroimagem/métodos , Animais , Modelos Animais de Doenças , Ratos
13.
Angew Chem Int Ed Engl ; 57(50): 16544-16548, 2018 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-30358035

RESUMO

Organofluorine compounds are widely used in pharmaceutical, agrochemical, and materials sciences. The syntheses and applications of fluorinated organoborons facilitate the rapid and modular assemblies of fluorine-containing molecules because of the versatility of C-B bonds in diverse chemical transformations. Reported herein is a migratory geminal difluorination of aryl-substituted alkenyl N-methyliminodiacetyl (MIDA) boronates using commercially available Py⋅HF as the fluorine source and hyperiodine as the oxidant. The protocol offers facile access to α- and ß-difluorinated alkylboron compounds, both of which have previously been challenging to prepare. Mild reaction conditions, broad substrate scope, good functional-group tolerance, and moderate to good yields were observed. The utility of these products is demonstrated by further transformations of the C-B bond into other valuable functional groups.

14.
J Neurosci Res ; 96(12): 1876-1886, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30272825

RESUMO

The glymphatic system is a newly identified waste clearance pathway in brain discovered and investigated predominately using in vivo two-photon confocal microscopy. Magnetic resonance imaging (MRI), in contrast to two-photon confocal microscopy, provides dynamic and real-time pictures of the glymphatic system in whole brain. We employ MRI to investigate the response of the glymphatic system to the rate of infusion of Gd-DTPA (magnevist). Wistar rats were subjected to a surgery of inserting a tube into the cisterna magna for infusion during MRI. Three infusion rates were chosen for 20 min infusions of diluted magnevist into the cerebrospinal fluid (CSF) of rat brain. Glymphatic response was imaged using dynamic MRI 3D measurement for 5 hr. Robust correlations were found in all ventricles between the peak intensities of image enhancement and infusion rates, with additional correlations between the peak times of MRI image enhancement and infusion rates in the fourth ventricle. An infusion rate of 2.92 µL/min induced an evident accumulation of tracer in the fourth ventricle near the cisterna magna. In hippocampal tissue, image enhancements exhibited low correlation with the infusion rates. However, an infusion rate of 1.67 µL/min provided a high image enhancement, but less tracer accumulation near the cisterna magna. Contrast-enhanced MRI provides a suitable tool for investigating image contrast infusion rate response of the glymphatic system in rat brain. Considering both T1 and T2 * effects in response to the infused magnevist into CSF, the infusion rate of 1.67 µL/min appears suitable for MRI study of the glymphatic system in rat.


Assuntos
Gadolínio DTPA/administração & dosagem , Sistema Glinfático/diagnóstico por imagem , Sistema Glinfático/metabolismo , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Ventrículos Cerebrais/diagnóstico por imagem , Ventrículos Cerebrais/metabolismo , Cisterna Magna , Infusões Intraventriculares , Imagem por Ressonância Magnética/métodos , Masculino , Ratos , Ratos Wistar
15.
Angew Chem Int Ed Engl ; 57(40): 13096-13100, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30252190

RESUMO

A cobalt-catalyzed decarboxylative Negishi coupling reaction of redox-active aliphatic esters with organozinc reagents was developed. The method enabled efficient alkyl-aryl, alkyl-alkenyl, and alkyl-alkynyl coupling reactions under mild reaction conditions with no external ligand or additive needed. The success of an in situ activation protocol and the facile synthesis of the drug molecule (±)-preclamol highlight the synthetic potential of this method. Mechanistic studies indicated that a radical mechanism is involved.

16.
Chem Commun (Camb) ; 54(82): 11562-11565, 2018 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-30225492

RESUMO

A Cp*Co(iii)-catalyzed [5+2] C-H annulation reaction of 2-vinylphenols with ynamides was developed. The reaction led to the efficient synthesis of valuable 2-aminobenzoxepines in high regioselectivity. Mild reaction conditions, good functional group tolerance, and moderate to good yields were observed. The synthetic utility was demonstrated by a gram-scale synthesis and further transformations of the products. Preliminary mechanistic studies were conducted, and a possible catalytic cycle was proposed.

17.
J Carbohydr Chem ; 47(5): 347-362, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30174372

RESUMO

Stereoselective formation of glycosidic bonds remains one of the most challenging topics in carbohydrate chemistry. The predominant method for stereoselective construction of 1,2-trans-glycosidic bonds is through the neighboring group participation effect (NGPE), which proved to be less successful in synthesizing Galß(1→3)GalNAc disaccharide. The steric effect that overshadows NGPE and the impacts of substituents at the 3-O- and 2-N-positions of donors and acceptors, respectively, on this synthesis were systematically examined to lead to some practical guidelines for choosing protecting groups towards the successful synthesis of Galß(1→3)GalNAc and similar disaccharides.

18.
Molecules ; 23(7)2018 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-29966261

RESUMO

Many malignant cell surface carbohydrates resulting from abnormal glycosylation patterns of certain diseases can serve as antigens for the development of vaccines against these diseases. However, carbohydrate antigens are usually poorly immunogenic by themselves, thus they need to be covalently coupled with immunologically active carrier molecules to be functional. The most well established and commonly used carriers are proteins. In recent years, the use of toll-like receptor (TLR) ligands to formulate glycoconjugate vaccines has gained significant attention because TLR ligands can serve not only as carrier molecules but also as built-in adjuvants to form fully synthetic and self-adjuvanting conjugate vaccines, which have several advantages over carbohydrate-protein conjugates and formulated mixtures with external adjuvants. This article reviews recent progresses in the development of conjugate vaccines based on TLR ligands. Two major classes of TLR ligands, lipopeptides and lipid A derivatives will be covered with more focus on monophosohoryl lipid A (MPLA) and related analogs, which are TLR4 ligands demonstrated to be able to provoke T cell-dependent, adaptive immune responses. Corresponding conjugate vaccines have shown promising application potentials to multiple diseases including cancer.


Assuntos
Glicoconjugados , Receptores Toll-Like/imunologia , Vacinas/imunologia , Adjuvantes Imunológicos , Animais , Portadores de Fármacos , Epitopos de Linfócito T/imunologia , Glicoconjugados/química , Glicosilação , Humanos , Ligantes , Lipídeo A , Lipopeptídeos , Receptores Toll-Like/metabolismo , Vacinas/química , Vacinas Sintéticas/química , Vacinas Sintéticas/imunologia
19.
Chem Commun (Camb) ; 54(46): 5907-5910, 2018 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-29789842

RESUMO

A novel synthesis of α-CF3 and α-CF2H amines via the aminofluorination of gem-difluoroalkenes and mono-fluoroalkenes, respectively, is reported. The method employs Selectfluor as an electrophilic fluorine source and acetonitrile as a nitrogen source. Mechanistic studies revealed a single-electron oxidation/fluorine-abstraction/Ritter-type amination pathway. The protocol allowed the synthesis of a broad range of fluorinated amines including those bearing quaternary carbon centers with good efficiency and functional group tolerance.

20.
Org Lett ; 20(7): 1924-1927, 2018 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-29552884

RESUMO

A reductive cross-coupling of gem-difluoroalkenes with diverse unactivated and heteroatom substituted olefins through a Fe-catalyzed hydrogen atom transfer (HAT) strategy is reported. Different from the previous HAT-type olefin cross-coupling reactions, the presence of a fluorine atom in the molecule results in a stereoselective ß-F cleavage, leading to a C(sp2)-C(sp3) bond formation. A wide variety of alkylated monofluoroalkenes were obtained in good efficiency with excellent Z selectivity under air- and water-tolerant reaction conditions. A similar defluorinative coupling reaction of monofluoroalkenes was also realized.

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