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1.
Org Lett ; 26(37): 7891-7896, 2024 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-39240619

RESUMO

In this paper, novel sulfur-containing 1,6-dihydrofuro[3,2-b]pyrazolo[3,4-e][1,4]thiazine skeletons were constructed from the simple and readily available materials enaminone, 5-aminopyrazole, and 1,4-dithiane-2,5-diol. Furthermore, a novel 1,4-dithiane-2,5-diol reaction mode has been developed through a double-dipole-reversal process induced by iodine that results in the formation of six new bonds and two new rings in a one-pot reaction. This method shows good substrate compatibility, and the products can be further modified with a variety of pharmaceuticals. Additionally, this novel skeleton exhibits good fluorescence properties in solution, enabling bright and stable green fluorescence imaging in HeLa cells.

2.
J Org Chem ; 88(16): 12000-12012, 2023 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-37540765

RESUMO

An I2-DMSO-mediated multicomponent [3+1+2] cascade annulation reaction using aryl methyl ketones, enaminones, and benzo[d]isoxazol-3-amine as substrates has been developed. This metal-free reaction involved the transannulation of benzo[d]isoxazol-3-amines with the formation of two C-N bonds and a C-C bond in one pot. Notably, a pyrimidine ring with a 1,4-dicarbonyl scaffold could efficiently transform into a pyrimido[4,5-d]pyridazine skeleton. The phenolic hydroxyl group of the target product could undergo further modification with pharmaceuticals, demonstrating the utility of this method.

3.
J Pharm Anal ; 13(7): 776-787, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37577390

RESUMO

Against tumor-dependent metabolic vulnerability is an attractive strategy for tumor-targeted therapy. However, metabolic inhibitors are limited by the drug resistance of cancerous cells due to their metabolic plasticity and heterogeneity. Herein, choline metabolism was discovered by spatially resolved metabolomics analysis as metabolic vulnerability which is highly active in different cancer types, and a choline-modified strategy for small molecule-drug conjugates (SMDCs) design was developed to fool tumor cells into indiscriminately taking in choline-modified chemotherapy drugs for targeted cancer therapy, instead of directly inhibiting choline metabolism. As a proof-of-concept, choline-modified SMDCs were designed, screened, and investigated for their druggability in vitro and in vivo. This strategy improved tumor targeting, preserved tumor inhibition and reduced toxicity of paclitaxel, through targeted drug delivery to tumor by highly expressed choline transporters, and site-specific release by carboxylesterase. This study expands the strategy of targeting metabolic vulnerability and provides new ideas of developing SMDCs for precise cancer therapy.

4.
Anal Chem ; 95(17): 6775-6784, 2023 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-37021399

RESUMO

Metabolic perturbation score-based mass spectrometry imaging (MPS-MSI) is proposed to reveal the spatially resolved functional metabolic response associated with disease progression or drug action including metabolism pathways, species, biofunction, or biotransformation. The MPS-MSI enables the exploration of therapeutic or adverse effects, regional heterogeneous responses to drug treatment, possible molecular mechanisms, and even drug potential targets. MPS-MSI was demonstrated to be a promising molecular imaging tool not only for efficacy and safety evaluation but also for molecular mechanism investigation at the early stage of drug research and development.


Assuntos
Imagem Molecular , Espectrometria de Massas/métodos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
5.
Toxicol Appl Pharmacol ; 460: 116378, 2023 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-36641037

RESUMO

Ginsenosides are the main bioactive constituents of Panax ginseng, which have been broadly studied in cancer treatment. Our previous studies have demonstrated that 3ß-O-Glc-DM (C3DM), a biosynthetic ginsenoside, exhibited antitumor effects in several cancer cell lines with anti-colon cancer activity superior to ginsenoside 20(R)-Rg3 in vivo. However, the efficacy of C3DM on glioma has not been proved yet. In this study, the antitumor activities and underlying mechanisms of C3DM on glioma were investigated in vitro and in vivo. Cell viability, apoptosis, migration, FCM, IHC, RT-qPCR, quantitative proteomics, and western blotting were conducted to evaluate the effect of C3DM on glioma cells. ADP-Glo™ kinase assay was used to validate the interaction between C3DM and EGFR. Co-cultured assays, lactic acid kit, and spatially resolved metabolomics were performed to study the function of C3DM in regulating glioma microenvironment. Both subcutaneously transplanted syngeneic models and orthotopic models of glioma were used to determine the effect of C3DM on tumor growth in vivo. We found that C3DM dose-dependently induced apoptosis, and inhibited the proliferation, migration and angiogenesis of glioma cells. C3DM significantly inhibited tumor growth in both subcutaneous and orthotopic mouse glioma models. Moreover, C3DM attenuated the acidified glioma microenvironment and enhanced T-cell function. Additionally, C3DM inhibited the kinase activity of EGFR and influenced the EGFR/PI3K/AKT/mTOR signaling pathway in glioma. Overall, C3DM might be a promising candidate for glioma prevention and treatment.


Assuntos
Ginsenosídeos , Glioma , Camundongos , Animais , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ginsenosídeos/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Microambiente Tumoral , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Glioma/metabolismo , Modelos Animais de Doenças , Receptores ErbB/metabolismo , Linhagem Celular Tumoral , Proliferação de Células
6.
Org Lett ; 24(46): 8573-8577, 2022 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-36378685

RESUMO

An I2-DMSO mediated multicomponent [3+2] cascade annulation reaction using methyl ketones, 1,2,3,4-tetrahydroisoquinolines (THIQ) and cyclopropenones as readily available substrates has been developed. This metal-free process involves N-H/α-C(sp3)-H trifunctionalization of THIQ and C-C bond cleavage of cyclopropenone, providing a direct approach to obtain pyrrolo[2,1-a]isoquinoline derivatives with a quaternary carbon center. Two C-C bonds and one C-N bond are formed efficiently in one pot.

7.
Org Lett ; 24(15): 2858-2862, 2022 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-35394795

RESUMO

An I2-DMSO-mediated cascade reaction using methyl ketones and 1,2,3,4-tetrahydroisoquinolines (THIQs) as commercially available substrates has been developed for the construction of pyrrolo[2,1-a]isoquinoline derivatives. This metal-free process involves N-H/α-C(sp3)-H difunctionalization of THIQ. Two C-C bonds and one C-N bond are formed in one pot under mild conditions. Besides, a quaternary carbon center has been constructed in this transformation efficiently.

8.
Mater Horiz ; 8(2): 547-555, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-34821270

RESUMO

By integrating high molecular rigidity and stable chirality, two pairs of D*-A type circularly polarized thermally activated delayed fluorescence (CP-TADF) emitters with an almost absolute quasi-equatorial conformer geometry and excellent photoluminescence quantum efficiencies (PLQYs) are developed, achieving state-of-the-art electroluminescence performance among blue and orange circularly polarized organic light-emitting diodes (CP-OLEDs).

9.
Bioorg Chem ; 111: 104973, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34004586

RESUMO

Parthenolide and micheliolide have attracted great attention in anticancer research due to their unique activities. In this study, thirteen parthenolide derivatives and twenty-three micheliolide derivatives were synthesized. Most synthesized compounds showed higher cytotoxicity than parthenolide or micheliolide. The in vivo anticancer activity of several representative compounds was evaluated in mice. One micheliolide derivative, 9-oxomicheliolide (43), showed promising in vivo antitumor activity compared with clinical drugs cyclophosphamide or temozolomide. Compound 43 was particularly effective against glioblastoma, with its tumor inhibition rate in mice comparable to the drug temozolomide. The discovery of compound 43 also demonstrates the feasibility of developing anticancer micheliolide derivatives by modification at C-9 position. Anticancer mechanism studies revealed that 9-oxomicheliolide exhibited inhibition effect against NF-κB and STAT3 signaling pathways, as well as induction effects of cell apoptosis. It is postulated that 9-oxomicheliolide is likely to be a modulator of the immune system, which regulates the anticancer immune responses.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , NF-kappa B/antagonistas & inibidores , Fator de Transcrição STAT3/antagonistas & inibidores , Sesquiterpenos de Guaiano/farmacologia , Sesquiterpenos/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , NF-kappa B/metabolismo , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Fator de Transcrição STAT3/metabolismo , Sesquiterpenos/síntese química , Sesquiterpenos/química , Sesquiterpenos de Guaiano/síntese química , Sesquiterpenos de Guaiano/química , Relação Estrutura-Atividade , Células Tumorais Cultivadas
10.
Angew Chem Int Ed Engl ; 59(25): 9972-9976, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31710142

RESUMO

Current research on thermally activated fluorescence (TADF) emitters is mainly based on the molecular levels, while the aggregation states of TADF emitters are to be explored deeply. Now two multifunctional emitters are reported with simultaneous TADF, aggregation induced emission (AIE), and multicolor mechanochromic luminescence (MCL) features. Both emitters also show polymorph-dependent TADF emission. Crystal structure analysis reveals that the polymorphism is ascribed to the mutable conformations in different aggregation states. This work brings new insight to TADF emitters from a perspective of aggregation states.

11.
Chem Commun (Camb) ; 54(84): 11897-11900, 2018 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-30276382

RESUMO

A molecular iodine-mediated formal [2+1+1+1] cycloaddition for the efficient synthesis of pyrrolo[2,1-a]isoquinolines from acetophenones, 1,2,3,4-tetrahydroisoquinoline (THIQ) and DMSO has been developed. Mechanistic studies revealed that DMSO served as the methylene source, and this novel protocol involves intermolecular cycloaddition of two in situ generated intermediates that enable efficient formation of one C-N bond and three C-C bonds via multiple sequential C-H functionalizations.

12.
Org Lett ; 19(9): 2262-2265, 2017 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-28421772

RESUMO

A novel one-pot reaction has been developed for the efficient synthesis of pyrrolo[2,1-a]isoquinolines and 1-dearyllamellarin core from (E)-(2-nitrovinyl)benzenes and azomethine ylides generated in situ. This strategy provides a concise total synthesis of the lamellarin core and lamellarin G trimethyl ether using electrophilic substitution and palladium-catalyzed Suzuki-Miyaura cross-coupling reactions.

13.
Org Lett ; 18(15): 3526-9, 2016 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-27396906

RESUMO

A one-pot acid-mediated reaction has been developed for the N-H/α,ß-C(sp(3))-H trifunctionalization of pyrrolidine without any metallic reagents or external oxidants. This reaction involves the intermolecular [3 + 2] cycloaddition of in situ-generated azomethine ylides with acrylic esters to provide facile access to 2,3-dihydro-1H-pyrrolizine derivatives in high yields under mild conditions.

14.
Org Lett ; 18(15): 3762-5, 2016 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-27463418

RESUMO

A transition-metal-free coupling annulation reaction of arynes, ketones, and alkynoates has been demonstrated. Using this formal [2 + 2 + 2] cycloaddition reaction, a wide variety of naphthalene derivatives were conveniently constructed in one pot with high efficiency. In addition, this novel and valid annulation has been successfully applied to the synthesis of 1-phenanthrenol derivatives.

15.
Org Lett ; 18(2): 196-9, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26700265

RESUMO

A transition-metal-free multicomponent coupling cyclization reaction was explored involving arynes, tosylhydrazine, and α-bromo ketones. The reaction proceeds via a formal [2 + 2 + 2] cycloaddition, giving access to cinnoline derivatives in moderate yields under mild conditions. Three chemical bonds were formed-two C-N bonds and one C-C bond-in a single step.


Assuntos
Compostos Heterocíclicos com 2 Anéis/química , Hidrocarbonetos Bromados/química , Imidas/química , Cetonas/química , Catálise , Ciclização , Estrutura Molecular , Estereoisomerismo
16.
Org Lett ; 17(21): 5216-9, 2015 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-26473636

RESUMO

A transition-metal-free multicomponent benzannulation reaction was developed from readily available ketones, nitro-olefins, and diester acetylenedicarboxylate. This approach provides a straightforward and efficient way to construct polysubstituted benzene derivatives under mild conditions in high yields.

17.
Org Lett ; 17(8): 1914-7, 2015 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-25826709

RESUMO

A multicomponent reaction has been developed for the synthesis of polyfunctional pyrazole derivatives from readily available arylglyoxal monohydrates, tosylhydrazine, and aldehydes or ketones. This synthetic method has significant advantages in broad substrate scope, excellent regioselectivity, and simple operation.


Assuntos
Pirazóis/síntese química , Aldeídos/química , Glioxal/análogos & derivados , Glioxal/química , Hidrazinas/química , Cetonas/química , Estrutura Molecular , Pirazóis/química , Estereoisomerismo
18.
Org Biomol Chem ; 13(17): 4976-80, 2015 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-25821120

RESUMO

A highly efficient method for the synthesis of 2-hydroxy-2,3-dihydrofuran derivatives from 1,4-enediones and phenacyl pyridinium halides via a domino reaction has been developed. This is a simple and beneficial strategy for the construction of 2-hydroxy-2,3-dihydrofuran compounds from readily available starting materials under mild conditions. Moreover, the application of this reaction provides a straightforward and practical route for the synthesis of the novel 4-(1H-pyrazol-4-yl)pyridazine skeleton.


Assuntos
Furanos/química , Hidrocarbonetos Halogenados/química , Cetonas/química , Pirazóis/síntese química , Piridazinas/síntese química , Compostos de Piridínio/química , Cristalografia por Raios X , Modelos Moleculares , Estrutura Molecular , Pirazóis/química , Piridazinas/química
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