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1.
Fitoterapia ; 140: 104412, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31698060

RESUMO

Aconitum carmichaelii has been used in traditional Chinese medicine for treating various diseases for several thousand years. Based on the biosynthetic pathway of some alkaloids such as C19-diterpenoid alkaloids and obvious differences in alkaloid content between leaves of two A. carmichaelii varieties has been reported, we performed leaves transcriptome analysis of two A. carmichaelii varieties. Besides we characterized the biosynthetic pathway of salsolinol. A total of 56 million raw reads (8.28 G) and 55 million clean reads (8.24 G) were obtained from two varieties (Z175 and R184) leaves transcriptome, respectively, and 176,793 unigenes were annotated. 281 and 843 unigenes are involved in the salsolinol biosynthetic pathway and the formation of C19-diterpenoid alkaloids respectively. And including 34 and 24 unigenes are the differentially expressed genes (DEGs) in the biosynthesis pathway for C19-diterpenoid alkaloids and salsolinol between Z175 and R184 respectively, which were target genes to explore differences in C19-diterpenoid alkaloid and salsolinol biosynthesis in Z175 and R184. Thus genes involved in alkaloid biosynthesis and accumulation differ between varieties leaves. The mechanisms underlying the differences and their relevance require further exploration. The results expand our knowledge of alkaloids biosynthesis in A. carmichaelii leaves, and provide a theoretical basis for analysis differences in alkaloids biosynthesis patterns in different varieties.


Assuntos
Aconitum/química , Vias Biossintéticas , Isoquinolinas/química , Transcriptoma , Alcaloides/biossíntese , China , Diterpenos/química , Perfilação da Expressão Gênica , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Folhas de Planta/química , Plantas Medicinais/química
2.
Chem Commun (Camb) ; 55(95): 14275-14278, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31720595

RESUMO

The amelioration of antibacterial efficacy along with the reduced minimum inhibitory concentration (MIC) of sanguinarine (SGR) drug have been demonstrated through the uptake of SGR by p-sulfonatocalix[6]arene functionalized silver nanoparticles. The large upward pKa shift and enhanced stability of SGR resulting from the favorable supra-nanomolecular strategy are deciphered into an improved antibacterial drug against different pathogenic micro-organisms including multi drug resistant bacteria.


Assuntos
Antibacterianos/farmacologia , Benzofenantridinas/farmacologia , Calixarenos/química , Escherichia coli/efeitos dos fármacos , Isoquinolinas/farmacologia , Nanopartículas Metálicas/química , Fenóis/química , Prata/química , Staphylococcus aureus/efeitos dos fármacos , Células A549 , Animais , Antibacterianos/química , Benzofenantridinas/química , Células CHO , Sobrevivência Celular/efeitos dos fármacos , Cricetulus , Sinergismo Farmacológico , Humanos , Isoquinolinas/química , Testes de Sensibilidade Microbiana , Tamanho da Partícula , Propriedades de Superfície
3.
Chem Commun (Camb) ; 55(98): 14765-14768, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31754664

RESUMO

BCL-XL, an anti-apoptotic BCL-2 family protein, plays a key role in cancer cell survival. However, the potential of BCL-XL as an anti-cancer target has been hampered by the on-target platelet toxicity because platelets depend on BCL-XL to maintain their viability. Here we report the development of a PROTAC BCL-XL degrader, XZ424, which has increased selectivity for BCL-XL-dependent MOLT-4 cells over human platelets compared with conventional BCL-XL inhibitors. This proof-of-concept study demonstrates the potential of utilizing a PROTAC approach to achieve tissue selectivity.


Assuntos
Isoquinolinas/química , Talidomida/análogos & derivados , Proteína bcl-X/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/química , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Apoptose/efeitos dos fármacos , Plaquetas/citologia , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Linhagem Celular Tumoral , Humanos , Isoquinolinas/metabolismo , Isoquinolinas/farmacologia , Ligação Proteica , Talidomida/química , Talidomida/metabolismo , Talidomida/farmacologia , Proteína bcl-X/antagonistas & inibidores
4.
J Agric Food Chem ; 67(35): 9796-9804, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31393712

RESUMO

Overactivated microglia and persistent neuroinflammation hold an important role in the pathophysiology of neurodegenerative diseases. The extract of Lycoris chejuensis (CJ) and its active compound, 7-deoxy-trans-dihydronarciclasine (named E144), attenuated expressions of pro-inflammatory factors, including nitric oxide, prostaglandin E2, inducible nitric oxide synthase, cyclooxygenase-2 (COX-2), tumor necrosis factor α (TNF-α), and interleukin 6, secreted by lipopolysaccharide-activated BV-2 microglial cells, as measured by an enzyme-linked immunosorbent assay or western blotting. In contrast, CJ extract and E144 promoted the secretion of the anti-inflammatory cytokine, interleukin 10. Moreover, we found that E144 attenuated the expression of TNF-α and COX-2 in the cerebral cortex of lipopolysaccharide-treated mice and/or T2576 transgenic mice as well as reduced the reactive immune cells visualized by ionized calcium-binding adaptor molecule 1. Our results suggest the possibility of E144 to serve as a potential anti-neuroinflammatory agent by preventing excess production of pro-inflammatory factors.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/imunologia , Isoquinolinas/administração & dosagem , Lycoris/química , Extratos Vegetais/administração & dosagem , Doença de Alzheimer/genética , Animais , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/imunologia , Modelos Animais de Doenças , Humanos , Interleucina-6/genética , Interleucina-6/imunologia , Isoquinolinas/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/metabolismo , NF-kappa B/genética , NF-kappa B/imunologia , Extratos Vegetais/química , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
5.
Molecules ; 24(15)2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31366067

RESUMO

NCMN (N-(3-carboxy propyl)-4-methoxy-1,8-naphthalimide), a newly developed ratiometric two-photon fluorescent probe for human Cytochrome P450 1A (CYP1A), shows the best combination of specificity and reactivity for real-time detection of the enzymatic activities of CYP1A in complex biological systems. This study aimed to investigate the interspecies variation in NCMN-O-demethylation in commercially available liver microsomes from human, mouse, rat, beagle dog, minipig and cynomolgus monkey. Metabolite profiling demonstrated that NCMN could be O-demethylated in liver microsomes from all species but the reaction rate varied considerably. CYP1A was the major isoform involved in NCMN-O-demethylation in all examined liver microsomes based on the chemical inhibition assays. Furafylline, a specific inhibitor of mammalian CYP1A, displayed differential inhibitory effects on NCMN-O-demethylation in all tested species. Kinetic analyses demonstrated that NCMN-O-demethylation in liver microsomes form rat, minipig and cynomolgus monkey followed biphasic kinetics, while in liver microsomes form human, mouse and beagle dog obeyed Michaelis-Menten kinetics, the kinetic parameters from various species are much varied, while NCMN-O-demethylation in MLM exhibited the highest similarity of specificity, kinetic behavior and intrinsic clearance as that in HLM. These findings will be very helpful for the rational use of NCMN as a practical tool to decipher the functions of mammalian CYP1A or to study CYP1A associated drug-drug interactions in vivo.


Assuntos
Citocromo P-450 CYP1A1/metabolismo , Desmetilação/efeitos dos fármacos , Corantes Fluorescentes/metabolismo , Isoquinolinas/metabolismo , Microssomos Hepáticos/enzimologia , Animais , Biotransformação/efeitos dos fármacos , Citocromo P-450 CYP1A1/antagonistas & inibidores , Citocromo P-450 CYP1A1/química , Inibidores das Enzimas do Citocromo P-450/farmacologia , Cães , Corantes Fluorescentes/química , Humanos , Isoquinolinas/química , Cinética , Macaca fascicularis , Camundongos , Ratos , Ratos Sprague-Dawley , Especificidade da Espécie , Suínos , Porco Miniatura , Teofilina/análogos & derivados , Teofilina/farmacologia
6.
J Agric Food Chem ; 67(33): 9286-9294, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31339733

RESUMO

Natural aryl hydrocarbon (AHR) ligands have been identified in food and herbal medicines, and they may exhibit beneficial activity in humans. In this study, white button (WB) feeding significantly decreased AHR target gene expression in the small intestine of both conventional and germ-free mice. High-performance liquid chromatography (HPLC) fractionation and ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) combined with an AHR-responsive cell-based luciferase gene reporter assay were used to isolate and characterize benzothiazole (BT) derivatives and 6-methylisoquinoline (6-MIQ) as AHR modulators from WB mushrooms. The study showed dose-dependent changes of AHR transformation determined by the cell-based luciferase gene reporter assay and transcription of CYP1A1 in human Caco-2 cells by BT derivatives and 6-MIQ. These findings suggested that WB mushroom contains new classes of natural AHR modulators and demonstrated HPLC fractionation and UHPLC-MS/MS combined with a cell-based luciferase gene reporter assay as a useful approach for isolation and characterization of the previously unidentifed AHR modulators from natural products.


Assuntos
Agaricus/química , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Receptores de Hidrocarboneto Arílico/genética , Animais , Benzotiazóis/química , Benzotiazóis/isolamento & purificação , Benzotiazóis/farmacologia , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Genes Reporter , Humanos , Isoquinolinas/química , Isoquinolinas/isolamento & purificação , Isoquinolinas/farmacologia , Ligantes , Camundongos , Extratos Vegetais/farmacologia , Receptores de Hidrocarboneto Arílico/metabolismo , Espectrometria de Massas em Tandem , Ativação Transcricional/efeitos dos fármacos , Verduras/química
7.
Dalton Trans ; 48(30): 11469-11479, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31290881

RESUMO

Two rhodium complexes Rh1 and Rh2 with isoquinoline derivatives were synthesized and characterized. Both complexes displayed strong anticancer activity against various cancer cells and low cytotoxicity against non-cancer cells. These complexes triggered apoptosis via mitochondrial dysfunction that increased the levels of ROS and Ca2+ and released cytochrome C which ultimately activated caspases and the apoptosis pathway. The different biological activities of Rh1 and Rh2 could be associated with the presence of methoxy substituents on the ligands. In vivo studies showed that Rh1 effectively inhibited tumor growth in a T-24 xenograft mouse model with a less adverse effect than cisplatin. Overall, Rh1 and Rh2 induced apoptosis via mitochondrial pathways and could be developed as effective anticancer agents.


Assuntos
Antineoplásicos/química , Isoquinolinas/química , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Ródio/química , Animais , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Transporte Biológico , Cálcio/metabolismo , Caspases/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ativação Enzimática/efeitos dos fármacos , Humanos , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Modelos Moleculares , Conformação Molecular , Compostos Organometálicos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Molecules ; 24(15)2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31357480

RESUMO

We have previously shown that compound-7g inhibits colorectal cancer cell proliferation and survival by inducing cell cycle arrest and PI3K/AKT/mTOR pathway blockage. However, whether it has the ability to exert antitumor activity in other cancer cells and what is the exact molecular mechanism for its antiproliferation effect remained to be determined. In the present study, compound-7g exhibited strong activity in suppressing proliferation and growth of glioblastoma cells. The inhibitor selectively downregulated F-box protein SKP2 expression and upregulated cell cycle inhibitor p27, and then resulted in G1 cell cycle arrest. Mechanism analysis revealed that compound-7g also provokes the down-regulation of E2F-1, which acts as a transcriptional factor of SKP2. Further results indicated that compound-7g induced an increase of LC3B-II and p62, which causes a suppression of fusion between autophagosome and lysosome. Moreover, compound-7g mediated autophagic flux blockage promoted accumulation of ubiquitinated proteins and then led to endoplasmic reticulum stress. Our study thus demonstrated that pharmacological inactivation of E2F-1-SKP2-p27 axis is a promising target for restricting cancer progression.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Benzimidazóis/química , Isoquinolinas/química , Proteínas Quinases Associadas a Fase S/genética , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Fator de Transcrição E2F1/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Proteólise
9.
Molecules ; 24(11)2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31185639

RESUMO

Herein we describe a very useful application of the readily available trifunctional aromatic ketone methyl-2-(2-bromoacetyl)benzoate in reactions with primary amines. An unexpected in situ air oxidation that follows a cascade process allowed the access to a series of isoquinoline-1,3,4(2H)-triones, a class of heterocyclic compounds of great interest containing an oxygen-rich heterocyclic scaffold. A modification of the original protocol, utilizing a Staudinger reaction in the presence of trimethylphosphine, was necessary for the synthesis of Caspase inhibitor trione with free NH group.


Assuntos
Ar , Isoquinolinas/química , Metais/química , Conformação Molecular , Oxirredução
10.
Chem Commun (Camb) ; 55(42): 5902-5905, 2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31045188

RESUMO

Multifunctional isoquinoline-oxazolines (MIQOXs) were conceived and synthesized from commercially available chiral amino acids. The multifunctional role of MIQOXs was demonstrated by Pd-catalyzed highly enantioselective addition of arylboronic acids to nitrostyrenes, and by the discovery of novel antifungal candidates.


Assuntos
Isoquinolinas/química , Oxazóis/química , Catálise , Ligantes , Estereoisomerismo
11.
Eur J Med Chem ; 174: 309-329, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31055147

RESUMO

Tuberculosis (TB) is a major infectious disease associated increasingly with drug resistance. Thus, new anti-tubercular agents with novel mechanisms of action are urgently required for the treatment of drug-resistant TB. In prior work, we identified compound 1 (cyclohexyl(4-(isoquinolin-5-ylsulfonyl)piperazin-1-yl)methanone) and showed that its anti-tubercular activity is attributable to inhibition of inosine-5'-monophosphate dehydrogenase (IMPDH) in Mycobacterium tuberculosis. In the present study, we explored the structure-activity relationship around compound 1 by synthesizing and evaluating the inhibitory activity of analogues against M. tuberculosis IMPDH in biochemical and whole-cell assays. X-ray crystallography was performed to elucidate the mode of binding of selected analogues to IMPDH. We establish the importance of the cyclohexyl, piperazine and isoquinoline rings for activity, and report the identification of an analogue with IMPDH-selective activity against a mutant of M. tuberculosis that is highly resistant to compound 1. We also show that the nitrogen in urea analogues is required for anti-tubercular activity and identify benzylurea derivatives as promising inhibitors that warrant further investigation.


Assuntos
Antituberculosos/farmacologia , Inibidores Enzimáticos/farmacologia , IMP Desidrogenase/antagonistas & inibidores , Isoquinolinas/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Piperazinas/farmacologia , Antituberculosos/síntese química , Antituberculosos/química , Domínio Catalítico , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , IMP Desidrogenase/química , Isoquinolinas/síntese química , Isoquinolinas/química , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Relação Estrutura-Atividade
12.
Acta Biochim Biophys Sin (Shanghai) ; 51(6): 607-614, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31074773

RESUMO

Gallbladder carcinoma (GBC) is the most common and aggressive cancer of the biliary tract. Liensinine has been proved to have hypotensive effect. However, the effect of liensinine on GBC is still unknown. The aim of this study is to investigate the effect and mechanism of liensinine in human GBC cells. Cell viability assay and colony formation assay were performed to assess cell growth and proliferation. Flow cytometry analysis was used to investigate cell cycle apoptosis in vitro. Hoechst 33342 staining was also used to evaluate cell apoptosis. Western blot analysis was used to determine the expression of proteins corresponding to the related cell cycle and apoptosis. The effect of liensinine treatment in vivo was experimented with xenografted tumors. We found that liensinine significantly inhibited the growth of GBC cells both in vivo and in vitro. In vitro, cell growth and proliferation were significantly suppressed by liensinine in a dose- and time-dependent manner. In vivo, liensinine inhibited tumor growth. Liensinine could induce GBC cells G2/M phase arrest by up-regulating the levels of Cyclin B1 and CDK1 proteins. Liensinine also affected GBC cell cycle progression and induced apoptosis by down-regulating phosphorylated protein kinase B (AKT), phosphorylated protein kinase B (p-AKT), phosphatidylinositol 3-kinase (PI3K), and Zinc finger X-chromosomal protein (ZFX) proteins. Liensinine induced G2/M arrest and apoptosis in gallbladder cancer, suggesting that liensinine might represent a novel and effective agent against gallbladder cancer.


Assuntos
Apoptose/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Neoplasias da Vesícula Biliar/tratamento farmacológico , Isoquinolinas/farmacologia , Fenóis/farmacologia , Proteínas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Neoplasias da Vesícula Biliar/metabolismo , Neoplasias da Vesícula Biliar/patologia , Humanos , Isoquinolinas/química , Fatores de Transcrição Kruppel-Like/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Nelumbo/química , Fenóis/química , Fosfatidilinositol 3-Quinases/metabolismo , Fitoterapia , Proteínas Proto-Oncogênicas c-akt/metabolismo
13.
Analyst ; 144(13): 4024-4032, 2019 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-31140476

RESUMO

A new dual functional turn-on chemosensor, 2,6-diformyl-4-methylphenol-di(isoquinolinyl-1-hydrazone) (HL), has been developed, which could highly selectively discriminate Mg2+ and Zn2+ in different solvent systems. The chemosensor HL exhibits rapid visual turn-on fluorescence enhancing recognition toward Mg2+/Zn2+, which is not interfered by other cations, especially for respective congeners Ca2+/Cd2+. The remarkable fluorescence enhancement (71-fold or 11-fold) was observed after adding Mg2+ in acetonitrile or Zn2+ in DMF-H2O solvent systems. Additionally such a solvent medium-controlled platform could achieve the quantitative determination of Mg2+ and Zn2+ quantitation with low detection limits of 2.97 × 10-8 M and 3.07 × 10-7 M, respectively. Furthermore, the turn-on fluorescence sensing mechanism is also investigated by 1H NMR, FT-IR and ESI-MS spectroscopy. Density functional theory (DFT) calculations derive optimized geometries of HL and its complexes. Notably, non-toxic HL also can be successfully applied as a visual probe for the practical determination of Mg2+/Zn2+ in MCF-7 cells, Zebrafish larvae, syrup and water samples, which might provide extensive application in biology and medicine fields.


Assuntos
Corantes Fluorescentes/química , Hidrazonas/química , Isoquinolinas/química , Magnésio/análise , Zinco/análise , Animais , Teoria da Densidade Funcional , Água Potável/análise , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Humanos , Hidrazonas/síntese química , Hidrazonas/toxicidade , Isoquinolinas/síntese química , Isoquinolinas/toxicidade , Lagos/análise , Limite de Detecção , Células MCF-7 , Modelos Químicos , Solventes/química , Espectrometria de Fluorescência/métodos , Peixe-Zebra
14.
Eur J Med Chem ; 176: 410-418, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31125895

RESUMO

Positron emission tomography (PET) imaging of the 18 kDa translocator protein (TSPO), has a high diagnostic potential in neurodegenerative disorders and cancer. However, TSPO is considered a challenge for molecular imaging due to the poor availability of suitable radiotracers with adequate pharmacokinetic properties. Here, we describe the development of a radiofluorinated pyridinyl isoquinoline analogue of the established TSPO PET tracer (R)-[11C]PK11195 with improved binding properties in all known human TSPO phenotypes. We conducted a complete preclinical evaluation using in vitro, in vivo and ex vivo methods to assess the performance of this novel radiotracer and observed high specific binding of the radiotracer to TSPO, as well as high metabolic stability. Therefore, we propose this radiolabeled compound for further evaluation in animal models as well as in clinical trials.


Assuntos
Isoquinolinas/metabolismo , Piridinas/metabolismo , Compostos Radiofarmacêuticos/metabolismo , Receptores de GABA/metabolismo , Animais , Feminino , Radioisótopos de Flúor/química , Humanos , Isoquinolinas/síntese química , Isoquinolinas/química , Isoquinolinas/farmacocinética , Marcação por Isótopo , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Piridinas/síntese química , Piridinas/química , Piridinas/farmacocinética , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Distribuição Tecidual
15.
Biomed Chromatogr ; 33(9): e4565, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31032988

RESUMO

In previous structure-activity relationship studies to identify new and selective 5-HT7 receptor (5-HT7 R) ligands, we identified the chiral compound, 5-chloro-2-{2-[3,4-dihydroisoquinoline-2(1H)-yl]ethyl}-2-methyl-2,3-dihydro-1H-inden-1-one (SYA 40247), with high-affinity binding to the 5-HT7 R. Thus, it was of interest to separate the enantiomers in order to evaluate their affinity at the 5-HT7 R. To achieve this separation, a normal-phase analytical method using HPLC-PDA and a 4.6 × 250 mm Chiralpak AD-H column was developed. Optimized isocratic conditions of 1.00 mL/min 95:5:0.1 v/v/v hexane-ethanol-diethylamine and a 254 nm analysis wavelength yielded a 6.07 min baseline separation. The method was scaled up to a 10 × 250 mm Chiralpak AD-H column, allowing 3 mg of racemate to be separated with a single injection, and 6 mg for an overlapping double injection in the same run. The separated enantiomers were reinjected into the analytical HPLC system, peak identities confirmed by retention time and PDA UV spectra, and the enantiomeric purities determined to be 100% for peak 1 and 100% for peak 2. A Jasco P-1020 polarimeter was used to determine the specific rotation [α] of the enantiomers of peaks 1 and 2, which were -86.2 and +93.3 (deg mL)/(g dm) respectively. No racemization was observed, and the enantiomeric purity remained at 100% for each peak.


Assuntos
Amilose/análogos & derivados , Cromatografia Líquida de Alta Pressão/métodos , Indenos/química , Indenos/isolamento & purificação , Isoquinolinas/química , Isoquinolinas/isolamento & purificação , Fenilcarbamatos/química , Amilose/química , Isoquinolinas/análise , Ligantes , Receptores de Serotonina/química , Receptores de Serotonina/metabolismo , Estereoisomerismo
16.
Org Lett ; 21(10): 3533-3537, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-31033297

RESUMO

The Pomeranz-Fritsch reaction and its Schlittler-Müller modification were successfully applied in the Ugi postcyclization strategy by using orthogonally protected aminoacetaldehyde diethyl acetal and complementary electron rich building blocks. Several scaffolds, including isoquinolines, carboline, alkaloid-like tetrazole-fused tetracyclic compounds, and benzo[ d]azepinone scaffolds, were synthesized in generally moderate to good yield. All our syntheses provide a short MCR-based sequence to novel or otherwise difficult to access scaffolds. Hence, we foresee multiple applications of these synthesis technologies.


Assuntos
Acetais/química , Alcaloides/química , Isoquinolinas/química , Tetrazóis/química , Estrutura Molecular
17.
Spectrochim Acta A Mol Biomol Spectrosc ; 219: 154-163, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31035125

RESUMO

A bifunctional organic compound 2-butyl-6-hydroxy-1,3-dioxo-2,3-dihydro-1H-benzo[de] isoquinoline-5-carbaldehyde (BHC) with photochromic properties in solid state and probe detection for ClO- in complete water solution was synthesized and fully characterized. A 'white-yellow-white' reversible photochromic behavior could be observed when alternating UV/vis light irradiation on the solid BHC powder. Good fatigue resistance and adjustable bleaching rate were shown when heating conditions changes. In addition, BHC displayed a high selectivity and low detection limit (1.16 × 10-8 M) for ClO-. The photoluminescent fluorescence "on-off" recognition result can be easily identified and BHC has been tested for safely imaging living cells and detecting hypochlorite anion in vitro and vivo. A better water solubility of BHC effectively reduces damage caused by organic solvent in cell imaging progress.


Assuntos
Aldeídos/química , Corantes Fluorescentes/química , Ácido Hipocloroso/análise , Isoquinolinas/química , Naftalimidas/química , Ânions/análise , Fluorescência , Células HeLa , Humanos , Modelos Moleculares , Imagem Óptica/métodos
18.
J Pharm Biomed Anal ; 170: 153-160, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-30925272

RESUMO

An effective strategy based on high-speed counter-current chromatography (HSCCC) knockout combination with HPLC-DAD-QTOF-MS/MS analysis were developed to identify minor lignans, alkaloids, and phenylpropanoid glycosides in M. officinalis. Petroleum ether/ethyl acetate/methanol/water (8:4:7:5, v/v/v/v) as solvent system was firstly selected to separate the crude extract of M. officinalis. Two major lignans, honokiol and magnolol were knocked out, and minor components were enriched. Then, five standards (honokiol, magnolol, magnocurarine, magnoflorine and acteoside) were used as examples to discuss their fragmentation patterns for structural identification. By comprehensive screening, sixteen lignans, nine alkaloids, six phenylpropanoid glycosides were unambiguously or tentatively identified by comparing their retention time, UV spectra, accurate mass and fragmentation patterns with standards or reported components. Eight of them, as far as was known, were discovered from M. officinalis for the first time. The proposed method might provide a model for the effective identification of minor components from complex herbs. Additionally, this study laid a foundation for the study of quality control, and clinical applications of M. officinalis.


Assuntos
Alcaloides/química , Glicosídeos/química , Lignanas/química , Magnolia/química , Propanóis/química , Aporfinas/química , Compostos de Bifenilo/química , Cromatografia Líquida de Alta Pressão/métodos , Glucosídeos/química , Isoquinolinas/química , Metanol/química , Fenóis/química , Espectrometria de Massas em Tandem/métodos
19.
Org Biomol Chem ; 17(11): 2923-2939, 2019 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-30801604

RESUMO

In this study, a small library of twenty benzo[g]isoquinoline-5,10-diones were synthesized in a novel straightforward approach, starting from 2-methyl-1,4-naphthoquinone (vitamin K). An intramolecular Heck reaction of a N-vinylacetamide was a crucial step in the synthetic route, at which the combination of cesium carbonate and a bulky, electron rich trialkylphosphine (tBuCy2P.HBF4) provided high 6-endo-trig selectivity. The anti-tubercular activity against Mycobacterium tuberculosis H37Ra and acute cytotoxicity against J774 A.1 macrophages were studied. From the structure activity relationship, it could be derived that in general the substitution of position 3 yielded analogs with a higher antitubercular potency. Among these, two analogs, 27a and 27b, showed remarkable activity with minimal inhibition concentrations of respectively 28.92 µM and 1.05 µM, and acute cytotoxic concentrations of >128 µM and 34.85 µM. In addition, the analogs and their possible metabolites were evaluated using a Vitotox™ assay to study the possibility of genotoxicity. Results indicated that none of the evaluated analogs and their possible metabolites showed early signs of genotoxicity.


Assuntos
Antituberculosos/síntese química , Antituberculosos/farmacologia , Isoquinolinas/farmacologia , Macrófagos/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Antituberculosos/química , Relação Dose-Resposta a Droga , Humanos , Isoquinolinas/síntese química , Isoquinolinas/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade
20.
Molecules ; 24(3)2019 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-30717460

RESUMO

Base-catalyzed annulation reactions of 5,6-dihydro-2(1H)-pyridones with Nazarov-type reagents are reported. The effect of the solvent polarity and the concentration of the reagents is studied. The process involves two successive Michael additions and stereoselectively provides functionalized cis-perhydroisoquinolin-1-ones.


Assuntos
Técnicas de Química Sintética , Peróxido de Hidrogênio/química , Isoquinolinas/química , Catálise , Isoquinolinas/síntese química , Modelos Moleculares , Conformação Molecular , Estrutura Molecular
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