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1.
Bioorg Med Chem ; 29: 115835, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33214037

RESUMO

A new one-pot two-step sequential methodology for synthesis of novel 3-carboxyethyl 4-[(tert-butylamino)methyl]-N-arylpyrazole derivatives is reported. One-pot transformation of ß-enamino diketones and arylhydrazines generated 4-iminium-N-arylpyrazole salt intermediates in situ, which were easily transformed into 4-[(tert-butylamino)methyl]-N-arylpyrazole derivatives by NaBH3CN. The products could be isolated in the free or hydrochloride salt forms. Also, it was possible to obtain the products in the zwitterionic form by ester group hydrolysis. Furthermore, all synthesised compounds were evaluated in vitro against a panel of eight human tumor cell lines. The 4-[(tert-butylamino)methyl]-N-arylpyrazole derivatives were much more powerful than the hydrochloride and zwitterionic forms. Moreover, the results suggest that the N-aryl group at the pyrazole ring is vital for modulating antiproliferative activity. The 3-carboxyethyl 4-[(tert-butylamino)methyl]-N-phenylpyrazoles 3a-g exhibited higher inhibitory activities against OVCAR-3, with GI50 values of 0.013-8.78 µM, and lower inhibitory activities against normal human cell lines. Molecular docking was performed to evaluate the probable binding mode of 3a into active site of CDK2.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Neoplasias Ovarianas/tratamento farmacológico , Pirazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Neoplasias Ovarianas/patologia , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-Atividade
2.
Bol. latinoam. Caribe plantas med. aromát ; 20(1): 51-60, 2021. tab, graf
Artigo em Inglês | LILACS, MOSAICO - Saúde integrativa | ID: biblio-1145969

RESUMO

El extracto de cloroformo (CE) y las fracciones obtenidas de las raíces de Aldama arenaria se evaluaron para determinar su actividad antiproliferativa in vitro contra 10 líneas celulares tumorales humanas [leucemia (K-562), mama (MCF-7), ovario que expresa un fenotipo resistente a múltiples fármacos (NCI/ADR-RES), melanoma (UACC-62), pulmón (NCI-H460), próstata (PC-3), colon (HT29), ovario (OVCAR-3), glioma (U251) y riñón (786-0)]. CE presentó actividad antiproliferativa débil a moderada (log GI50 medio 1.07), mientras que las fracciones 3 y 4, enriquecidas con diterpenos de tipo pimarane [ent-pimara-8 (14), ácido 15-dien-19-oico y ent-8(14),15-pimaradien-3ß-ol], presentaron actividad moderada a potente para la mayoría de las líneas celulares, con un log GI50 medio de 0.62 y 0.59, respectivamente. Los resultados mostraron una acción antiproliferativa in vitro prometedora de las muestras obtenidas de A. arenaria, con los mejores resultados para NCI/ADR-RES, HT29 y OVCAR-3, y valores de TGI que van desde 5.95 a 28.71 µg.mL-1, demostrando que los compuestos de esta clase pueden ser prototipos potenciales para el descubrimiento de nuevos agentes terapéuticos.


Chloroform extract (CE) and fractions obtained from Aldama arenaria roots were evaluated for their in vitro antiproliferative activity against 10 human tumor cell lines [leukemia (K-562), breast (MCF-7), ovary expressing a multidrug-resistant phenotype (NCI/ADR-RES), melanoma (UACC-62), lung (NCI-H460), prostate (PC-3), colon (HT29), ovary (OVCAR-3), glioma (U251), and kidney (786-0)]. CE presented weak to moderate antiproliferative activity (mean log GI50 1.07), whereas fractions 3 and 4, enriched with pimarane-type diterpenes [ent-pimara-8(14),15-dien-19-oic acid and ent-8(14),15-pimaradien-3ß-ol], presented moderate to potent activity for most cell lines, with mean log GI50 of 0.62 and 0.59, respectively. The results showed promising in vitro antiproliferative action of the samples obtained from A. arenaria, with the best results for NCI/ADR-RES, HT29, and OVCAR-3, and TGI values ranging from 5.95 to 28.71 µg.mL-1, demonstrating that compounds of this class may be potential prototypes for the discovery of new therapeutic agents.


Assuntos
Humanos , Arenaria (Planta)/química , Antineoplásicos , Plantas Medicinais , Técnicas In Vitro , Brasil , Extratos Vegetais , Cromatografia , Medicina Tradicional
3.
Molecules ; 25(17)2020 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-32899132

RESUMO

In the context of the cancer-inflammation relationship and the use of natural products as potential antitumor and anti-inflammatory agents, the alkaloid-enriched fraction of Boehmeriacaudata (BcAEF) aerial parts was evaluated. In vitro antiproliferative studies with human tumor cell lines showed high activity at low concentrations. Further investigation on NCI-H460 cells showed an irreversible effect on cell proliferation, with cell cycle arrest at G2/M phase and programmed cell death induction. Molecular docking studies of four alkaloids identified in BcAEF with colchicine's binding site on ß-tubulin were performed, suggesting (-)-C (15R)-hydroxycryptopleurine as the main inductor of the observed mitotic death. In vivo studies showed that BcAEF was able to reduce Ehrlich tumor volume progression by 30 to 40%. Checking myeloperoxidase activity, BcAEF reduced neutrophils migration towards the tumor. The in vivo anti-inflammatory activity was evaluated by chemically induced edema models. In croton oil-induced ear edema and carrageenan (CG)-induced paw edema models, BcAEF reduced edema around 70 to 80% together with inhibition of activation and/or migration of neutrophils to the inflammatory area. All together the results presented herein show BcAEF as a potent antitumor agent combining antiproliferative and anti-inflammatory properties, which could be further explored in (pre)clinical studies.


Assuntos
Alcaloides/química , Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Boehmeria/química , Simulação por Computador , Extratos Vegetais/farmacologia , Animais , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Clonais , Modelos Animais de Doenças , Orelha/patologia , Edema/patologia , Ativação Enzimática/efeitos dos fármacos , Exocitose , Humanos , Simulação de Acoplamento Molecular , Paclitaxel/farmacologia , Peroxidase/metabolismo , Fosfatidilserinas/metabolismo , Padrões de Referência , Testes de Toxicidade Aguda
4.
Chem Biodivers ; 16(5): e1800644, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30843651

RESUMO

The phytochemical investigation of Grazielia gaudichaudeana aerial parts yielded 15 compounds, including diterpenes, triterpenes, sterols and flavonoids. With exception to ent-kaurenoic acid diterpenes, the compounds isolated are being described for the first time in this species. Some unusual 1 H-NMR chemical shifts of 18-nor-ent-labdane (7-9) led us carry out a conformational analysis by theoretical calculations in order to support the experimental data. Moreover, due to the limitation of studies focused on pharmacological potential of Grazielia gaudichaudeana, the present study was carried out to investigate the antioxidant, antiproliferative, antiviral, antileishmanial and antimicrobial activities from the extract, fractions and isolated compounds obtained from this species. Ethyl acetate fraction showed significant activity in the antiproliferative assay, with GI50 range of 3.9 to 27.2 µg mL-1 . Dichloromethane fraction, rich in diterpenoids, inhibited all human tumor cell lines tested, and the nor-labdane 7 showed potent cytotoxic activity against glioma and ovary cancer cell lines.


Assuntos
Asteraceae/química , Diterpenos/química , Anti-Infecciosos/química , Anti-Infecciosos/isolamento & purificação , Anti-Infecciosos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/química , Antiprotozoários/química , Antiprotozoários/isolamento & purificação , Antiprotozoários/farmacologia , Asteraceae/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Fungos/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Leishmania/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Conformação Molecular , Extratos Vegetais/química
5.
Curr Pharm Biotechnol ; 20(4): 302-308, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30747062

RESUMO

BACKGROUND: The genus Psychotria and Palicourea are reported as a source of alkaloids and iridoids, which exhibit biological activities. This study aimed to evaluate antiproliferative and anticholinesterase activities and quantification of the alkaloids of seven species among the genus found in Mato Grosso do Sul region in Brazil. METHODS: Concentrations of alkaloids were measured spectrophotometrically. The extracts were submitted to antiproliferative activity against ten cell lines. The anticholinesterase activity of the extracts was developed using brain structures of male Wistar rats: cerebral cortex, hippocampus, hypothalamus and striatum by the Ellman method. RESULTS: Alkaloids from Psychotria and Palicourea species were quantified which showed values of 47.6 to 21.9 µg/g. Regarding the antiproliferative potential, Palicourea crocea demonstrated selectivity against the 786-0 cell line (GI50: 22.87 µg/mL). Psychotria leiocarpa inhibited cell growth against OVCAR-3 (GI50: 3.28 µg/mL), K-562 (GI50: 5.26 µg/mL), HaCaT (GI50: 27.20 µg/mL), PC-3 (GI50: 34.92 µg/mL), MCF-7 (GI50: 35.80 µg/mL) and P. capillacea showed activity against OVCAR-3 (GI50: 2.33 µg/ml) and U251 (GI50: 16.66 µg/ml). The effect of acetylcholinesterase inhibition was more effective in the hippocampus, demonstrating inhibition for Paliourea crocea, Psychotria deflexa, P. brachybotrya and P. leiocarpa of 70%, 57%, 50% and 40%, respectively, followed by P. poeppigiana and P. capillacea, inhibiting 21%, compared to the control. CONCLUSION: Herein, the present work showed for the first time, anticholinesterasic and antiproliferative activities of extracts of Palicourea and Psychotria seem to be mainly associated with the levels of alkaloids in the leaves of these species.


Assuntos
Alcaloides/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Inibidores da Colinesterase/farmacologia , Iridoides/farmacologia , Extratos Vegetais/farmacologia , Rubiaceae/química , Alcaloides/isolamento & purificação , Animais , Antineoplásicos Fitogênicos/isolamento & purificação , Brasil , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores da Colinesterase/isolamento & purificação , Hipocampo/efeitos dos fármacos , Hipocampo/enzimologia , Humanos , Iridoides/isolamento & purificação , Masculino , Extratos Vegetais/isolamento & purificação , Folhas de Planta/química , Ratos , Ratos Wistar , Rubiaceae/crescimento & desenvolvimento , Especificidade da Espécie
6.
Rev. bras. farmacogn ; 28(6): 703-709, Nov.-Dec. 2018. tab, graf
Artigo em Inglês | LILACS-Express | LILACS | ID: biblio-977748

RESUMO

ABSTRACT Plants are considered among the main sources of biologically active chemicals. The species Solidago chilensis Meyen, Asteraceae, is native to the southern parts of South America, where the aerial parts of the plant are commonly used for the treatment of inflammatory conditions. However, the effects of S. chilensis on human cancer cells remain to be elucidated. In this study, we evaluated the antiproliferative effects of the hydroalcoholic and dichloromethane extracts of S. chilensis, as well as their chemical constituents quercitrin and solidagenone against the five human tumor cell lines in vitro. The dichloromethane extract showed a promisor antiproliferative effects in vitro, especially against glioma cell line. Besides, the hydroalcoholic extract and quercitrin were inactive. The diterpene solidagenone showed highly potent antiproliferative effects against breast (MCF-7), kidney (786-0), and prostate cancer (PC-3) cells (total growth inhibition: TGI < 6.25 µg/ml). Solidagenone meets the theoretical physico-chemical criteria for bioavailability of drugs, according to the "Rule of Five" and, by theorical studies, the observed biological effects were probably related to the interaction of the molecule with nuclear receptors and as an enzymatic inhibitor. This study contributes to chemical study and to the identification of antiproliferative molecules in S. chilensis.

7.
Curr Pharm Biotechnol ; 19(12): 973-981, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30468122

RESUMO

BACKGROUND: Trichilia silvatica, popularly known as "catiguá-branco", is distributed in Brazil (Mato Grosso do Sul), and members of this genus are commonly used for the treatment of rheumatism (arthritis). The aim of this research was to investigate the anti-inflammatory, antioxidant and antiproliferative activities of the methanolic extract of the leaves (MEL-TS) and bark (MEB-TS) of T. silvatica. We also evaluated the concentration of phenolic compounds, flavonoids, flavonol, and condensed tannins by liquid chromatography - photodiode array (LC/PDA) analysis. METHODS: The MEL-TS and MEB-TS revealed the presence of caffeic acid in both extracts by LC/PDA. The samples were evaluated for antioxidant activity using free-radical scavenging and lipoperoxidation assays. The anti-inflammatory effects were studied in carrageenan-induced paw edema, pleurisy and zymosan-induced arthritis. RESULTS: The MEL-TS and MEB-TS showed the total phenolic concentration (270.8 ± 17.10 mg gallic acid equivalents GAE/g extract and 278.8 ± 25.13 mg GAE/ g extract, respectively), and flavonoids in MEL-TS (209.30 ± 2.91 mg quercetin equivalents QE/ g extract). In the lipoperoxidation assay, exhibited moderate antioxidant activity with IC50 values ≤ 35.32 µg/mL. Both extracts inhibited oedema induced by carrageenan at 2 h and 4 h, inhibited leukocyte migration at 6 h post administration, and did not impact zymosan-induced arthritis. Finally, MEL-TS was particularly effective against prostate cell line (GI50 ≤ 0.22 µg/mL). CONCLUSION: Overall, the results indicated that T. silvatica reduce migration leukocytes activity, edema formation in these models of experimental arthritis could explain the popular use for treatment of inflammatory processes (rheumatism).


Assuntos
Anti-Inflamatórios/isolamento & purificação , Antioxidantes/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Meliaceae/química , Extratos Vegetais/isolamento & purificação , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Compostos de Bifenilo/química , Brasil , Linhagem Celular Tumoral , Edema/tratamento farmacológico , Feminino , Radicais Livres/química , Humanos , Masculino , Meliaceae/crescimento & desenvolvimento , Camundongos , Picratos/química , Casca de Planta/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Pleurisia/tratamento farmacológico
8.
J Inorg Biochem ; 187: 85-96, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30081333

RESUMO

The bis-(1,10-phenanthroline)copper(I) complex, [Cu(I)(phen)2]+, was the first copper-based artificial nuclease reported in the literature. The biological and ligand-like properties of sulfonamides make them good candidates for fine-tuning the reactivity of the [Cu(phen)2] motif with biomolecules. In this context, we developed three novel copper(II) complexes containing the sulfonamides sulfameter (smtrH) and sulfadimethoxine (sdmxH) and (N^N)-bidentate ligands (2,2'-biyridine or 1,10-phenantroline). The compounds were characterized by chemical and spectroscopic techniques and single-crystal X-ray crystallography. When targeting plasmid DNA, the phen-containing compounds [Cu(smtr-)2(phen)] (1) and [Cu(sdmx-)2(phen)] (2) demonstrated nuclease activity even in the absence of reducing agents. Addition of ascorbic acid resulted in a complete cleavage of DNA by 1 and 2 at concentrations higher than 10 µM. Experiments designed to evaluate the copper intermediates involved in the nuclease effect after reaction with ascorbic acid identified at least the [Cu(I)(N^N)2]+, [Cu(I)(sulfa)(N^N)]+ and [Cu(I)(sulfa)2]+ species. The compounds interact with DNA via groove binding and intercalation as verified by fluorescence spectroscopy, circular dichroism (CD) and molecular docking. The magnitude and preferred mode of binding are dependent on the nature of both N^N ligand and the sulfonamide. The potent nuclease activity of compounds 1 and 2 are well correlated with their antiproliferative and anti-M. tuberculosis profiles. The results presented here demonstrated the potential for further development of copper(II)-sulfonamide-(N^N) complexes as multipurpose metallodrugs.


Assuntos
Antituberculosos , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação , Cobre , Desoxirribonucleases , Mycobacterium tuberculosis/crescimento & desenvolvimento , Sulfonamidas , Antituberculosos/síntese química , Antituberculosos/química , Antituberculosos/farmacologia , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacologia , Cobre/química , Cobre/farmacologia , Clivagem do DNA/efeitos dos fármacos , Desoxirribonucleases/síntese química , Desoxirribonucleases/química , Desoxirribonucleases/farmacologia , Humanos , Células K562 , Células MCF-7 , Simulação de Acoplamento Molecular , Sulfonamidas/química , Sulfonamidas/farmacologia
9.
Molecules ; 23(5)2018 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-29695037

RESUMO

Myrcia bella Cambess., Myrcia fallax (Rich.) DC. and Myrcia guianensis (Aubl.) DC. (Myrtaceae) are trees found in Brazilian Cerrado. They have been widely used in folk medicine for the treatment of gastrointestinal disorders, hemorrhagic and infectious diseases. Few reports have been found in the literature connecting their phenolic composition and biological activities. In this regard, we have profiled the main phenolic constituents of Myrcia spp. leaves extracts by ESI(−)Q-TOF-MS. The main constituents found were ellagic acid (M. bella), galloyl glucose isomers (M. guianensis) and hexahydroxydiphenic (HHDP) acid derivatives (M. fallax). In addition, quercetin and myricetin derivatives were also found in all Myrcia spp. extracts. The most promising antioxidant activity, measured by 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity, was found for M. fallax extracts (EC50 8.61 ± 0.22 µg·mL−1), being slightly less active than quercetin and gallic acid (EC50 2.96 ± 0.17 and 2.03 ± 0.02 µg·mL−1, respectively). For in vitro antiproliferative activity, M. guianensis showed good activity against leukemia (K562 TGI = 7.45 µg·mL−1). The best antimicrobial activity was observed for M. bella and M. fallax to Escherichia coli (300 and 250 µg·mL−1, respectively). In conclusion, the activities found are closely related to the phenolic composition of these plants.


Assuntos
Anti-Infecciosos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/farmacologia , Myrtaceae/química , Extratos Vegetais/farmacologia , Anti-Infecciosos/química , Antineoplásicos Fitogênicos/química , Antioxidantes/química , Linhagem Celular Tumoral , Sinergismo Farmacológico , Flavonóis/química , Flavonóis/farmacologia , Humanos , Redes e Vias Metabólicas , Testes de Sensibilidade Microbiana , Fenóis/química , Fenóis/farmacologia , Extratos Vegetais/química , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
10.
Rev. bras. farmacogn ; 27(5): 592-598, Sept.-Oct. 2017. tab, graf
Artigo em Inglês | LILACS-Express | LILACS | ID: biblio-898715

RESUMO

Abstract Natural products are a major source of drugs for the treatment of cancer. The species Alpinia zerumbet (Pers.) B.L. Burtt & R.M. Sm, Zingiberaceae, is widely distributed in Brazil where it is known as "colônia". The leaves are commonly used in the treatment of hypertension and dyspepsia, however, the effects of A. zerumbet extracts and isolated substances on human cancer cells remain to be elucidated. This study was designed to identify the chemical constituents of hydroalcoholic and dichloromethane extracts from A. zerumbet leaves and to investigate their in vitro antiproliferative activity. The isolated phytochemicals included kaempferol, dihydro-5,6-dehydrokavain, 5,6-dehydrokavain, and pinostrobin. The hydroalcoholic extract inhibited cellular proliferation only at high concentrations, while the dichloromethane extract showed a moderate antiproliferative effect against leukemia and lung tumor cell lines. 5,6-Dehydrokavain showed potent cytostatic activity against glioblastoma cells and a moderate effect on all other tumor cell lines. Pinostrobin showed potent activity against leukemia and breast tumor cell lines and moderate cytostatic effect against ovarian cell. Furthermore, this is the first report on the isolation of kaempferol and pinostrobin from A. zerumbet leaves. Moreover, the purification process described in this study was effective. These results suggest that A. zerumbet leaves are a promising source of anticancer compounds.

11.
An Acad Bras Cienc ; 88(3): 1201-9, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27598841

RESUMO

The cultivation of sugarcane hybrids (X Saccharum officinarum L.) is an important revenue source for the Brazilian economy. Herein it is reported the evaluation of the cytotoxic activity of mid-polarity sugarcane extracts against human cancer cell lines, as well as the isolation of steroids sitosterol, stigmasterol and campesterol, phenolic acids p-hydroxybenzoic, p-hydroxycinnamic, vanillic and ferulic acid, terpenoids α-tocopherol and ß-carotene and a novel substance in sugarcane, the flavonoid aglycone tricin (5,7,4-trihydroxy-3,5-dimethoxyflavone). The presence of large amounts of phenolic acids and the flavonoid tricin may explain the cytostatic activity observed for the mid-polarity crude extract and filtrates.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Fenóis/farmacologia , Extratos Vegetais/farmacologia , Saccharum/química , Antineoplásicos Fitogênicos/isolamento & purificação , Brasil , Linhagem Celular Tumoral , Humanos , Fenóis/isolamento & purificação , Extratos Vegetais/isolamento & purificação
12.
Food Chem ; 212: 695-702, 2016 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-27374586

RESUMO

Buttermilk is a dairy by-product with a high content of milk fat globule membranes (MFGMs), whose protein constituents are reported to be antiproliferative. Lipids represent about half of the composition of MFGM. The aim of this study was to isolate buttermilk lipid fractions and evaluate their potential antiproliferative effect. Selective extraction with food grade or non-food grade solvents was performed. Antiproliferative effectiveness of lipid extracts and their neutral and polar fractions was evaluated on nine human cancer cell lines. Fractions obtained using food grade ethanol gave a higher yield than those obtained using non-food grade solvents, and they effectively inhibited cell viability of the cancer cell lines investigated. These fractions, rich in phospho- and sphingolipids, were strongly antiproliferative against human ovary and colon cancer cells. This observation allowed us to hypothesize further analyses aimed at promoting the use of buttermilk polar lipid fractions as functional food additives.


Assuntos
Leitelho , Glicolipídeos/química , Glicoproteínas/química , Linhagem Celular , Linhagem Celular Tumoral/efeitos dos fármacos , Proliferação de Células , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Feminino , Conservação de Alimentos , Humanos , Gotículas Lipídicas , Lipídeos/análise , Lipídeos/química , Fosfolipídeos/química , Solventes/química , Esfingolipídeos/química
13.
Eur J Med Chem ; 111: 103-13, 2016 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-26859070

RESUMO

A series of novel isocoumarin derivatives were synthesized using Castro-Stephens cross-coupling. Moreover, novel 3,4-dihydroisocoumarin derivatives were obtained by catalytic hydrogenation of the corresponding isocoumarin precursors. The antiproliferative activity of all compounds was evaluated in vitro in different tumor cells. Furthermore, docking calculations were performed for the kallikrein 5 (KLK5) active site to predict the possible mechanism of action of this series of compounds. Theoretical findings indicate that the 3,4-dihydroisocoumarin derivative 10a forms hydrogen bonds with Ser190 and Gln192 residues of KLK5. This derivative was the most active compound in the series with potent antiproliferative activity and high selectivity index (SI > 378.79) against breast cancer cells (MCF-7, GI50 = 0.66 µg mL(-1)). This compound represents a promising matrix for developing new antiproliferative agents.


Assuntos
Antineoplásicos/farmacologia , Isocumarinas/química , Isocumarinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Isocumarinas/síntese química , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
14.
Eur J Med Chem ; 84: 595-604, 2014 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-25062010

RESUMO

Twelve novel 8-hydroxyquinoline derivatives were synthesized with good yields by performing copper-catalyzed Huisgen 1,3-dipolar cycloaddition ("click" reaction) between an 8-O-alkylated-quinoline containing a terminal alkyne and various aromatic or protected sugar azides. These compounds were evaluated in vitro for their antiproliferative activity on various cancer cell types. Protected sugar derivative 16 was the most active compound in the series, exhibiting potent antiproliferative activity and high selectivity toward ovarian cancer cells (OVCAR-03, GI50 < 0.25 µg mL(-1)); this derivative was more active than the reference drug doxorubicin (OVCAR-03, GI50 = 0.43 µg mL(-1)). In structure-activity relationship (SAR) studies, the physico-chemical parameters of the compounds were evaluated and docking calculations were performed for the α-glucosidase active site to predict the possible mechanism of action of this series of compounds.


Assuntos
Oxiquinolina/análogos & derivados , Oxiquinolina/farmacologia , Triazóis/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Células MCF-7 , Simulação de Dinâmica Molecular , Estrutura Molecular , Oxiquinolina/síntese química , Oxiquinolina/química , Relação Estrutura-Atividade , Triazóis/farmacologia
15.
Z Naturforsch C J Biosci ; 69(1-2): 46-52, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24772822

RESUMO

The Orchidaceae family is appreciated worldwide for the beauty of its flowers, and hundreds of species of this family occur in Brazil. Yet little is known about the potential of orchids for therapeutic application. We have investigated bioactive compounds produced by the South Brazilian orchid Miltonia flavescens Lindl. Bioguided studies with the fungus Cladosporium herbarum allowed the identification of hydrocinnamic acid as the active antifungal compound. In addition, the chloroform fraction exhibited an interesting activity against human cancer cells, and 5,7-dihydroxy-6,4'-dimethoxyflavone isolated from this fraction was found to be active against seven human cancer cell lines, including NCI/ADR-RES ovary sarcoma, with an IC50 value of 2.6 microg/mL. This is the first report on the cytostatic activity of this flavone against human ovary sarcoma.


Assuntos
Antifúngicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Orchidaceae/química , Extratos Vegetais/farmacologia , Cromatografia Gasosa-Espectrometria de Massas , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Espectrometria de Massas em Tandem
16.
Rev. bras. farmacogn ; 23(3): 441-446, May-June 2013. ilus, graf, tab
Artigo em Inglês | LILACS-Express | LILACS | ID: lil-676275

RESUMO

The cytotoxicity of a hexanic fraction produced from the ethanolic crude extract, obtained from Jatropha ribifolia (Pohl) Baill, Euphorbiaceae, roots was evaluated against ten human cancer cell lines (MCF-7, NCI-ADR/RES, OVCAR-3, PC-3, HT-29, NCI-H460,786-O, UACC-62, K-562, U251) compared with doxorrubicine as positive control. Compounds jatrophone and cyperenoic acid were isolated from the hexanic extract and characterized by spectroscopic techniques (NMR of ¹H, 13C and IR). The in vitro antiproliferative activity of jatrophone showed selectivity in a concentration dependent way with Total Inhibition growth of: glioma 0.57 µg mL-1 (U251), breast cancer 9.2 µg mL-1 (MCF-7), adriamycin-resistant ovarian cancer 0.96 µg mL-1 (NCI-ADR/RES), kidney 4.2 µg mL-1 (786-0), prostate cancer 8.4 µg mL-1 (PC-3), colon cancer 16.1 µg mL-1 (HT29) and leukemia 0.21 µg mL-1 (K-562).

17.
J Pharmacol Toxicol Methods ; 67(2): 121-8, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23000280

RESUMO

INTRODUCTION: The pharmacological assessment of the factors for gastric protection of a test substance should involve experimental models that can determine the involvement of cytoprotective factors, as well as their influence on the secretion of hydrochloric acid. The original protocol of pylorus ligation in rats proposed by Shay et al. in 1945, still in use today, provides a latency time of 240 min without considering the effect of postoperative pain in the mechanisms of peptic ulcer. This paper proposes a modification of this experimental protocol by eliminating the pain throughout the postoperative period, as a refinement of the test with consequent improvement of the pharmacological response. METHODS: Adult male Wistar/Uni rats underwent surgical ligation of the pylorus and were kept anesthetized throughout the experimental period (4h) in contrast to the other experimental groups that followed the original protocol proposed by Shay et al., 1945. RESULTS: We were able to determine effective doses for a positive control, as well as of a variety of secretagogues in the new experimental protocol proposed. DISCUSSION: The suppression of post-surgical pain, through the use of anesthesia throughout the experimental period, brought several benefits for the study of gastric acid secretion, rendering a more homogeneous pharmacologic response in non-inbred animals, thus being an effective experimental procedure.


Assuntos
Dor Pós-Operatória/prevenção & controle , Piloro/cirurgia , Úlcera Gástrica/induzido quimicamente , Animais , Betanecol/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ácido Gástrico/metabolismo , Mucosa Gástrica/metabolismo , Histamina/farmacologia , Ligadura , Masculino , Dor Pós-Operatória/fisiopatologia , Pentagastrina/farmacologia , Ratos , Ratos Wistar , Sensibilidade e Especificidade , Estômago/efeitos dos fármacos , Úlcera Gástrica/metabolismo , Úlcera Gástrica/patologia , Estresse Fisiológico/fisiologia
18.
Chemistry ; 18(52): 16890-901, 2012 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-23124578

RESUMO

Several syntheses have already been reported for cis-trikentrins and herbindoles, which are indole alkaloids unsubstituted at the C2 and C3 positions that bear a trans-1,3-dimethylcyclopentyl unit. Herein, we describe the first asymmetric and stereoselective synthesis of the more challenging trans-trikentrin A as its naturally occurring isomer. Different approaches were investigated and the strategy of choice was a combination of an enzymatic kinetic resolution and a thallium(III)-mediated ring contraction. The antiproliferative activities of the natural product and related intermediates have been tested against human tumor cell lines, leading to the discovery of new compounds with potent antitumor activity.


Assuntos
Antineoplásicos/síntese química , Descoberta de Drogas , Alcaloides Indólicos/síntese química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chlorocebus aethiops , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacologia , Estrutura Molecular , Estereoisomerismo , Células Vero
19.
Molecules ; 17(8): 9621-30, 2012 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-23442985

RESUMO

An efficient and concise synthesis of nine populene D analogues was performed using an iodine-catalyzed Prins cyclization as the key transformation. The antiproliferative activity of these new pyrans against several cancer cell lines was then investigated. Among them, an isochromene with moderate activity (mean logGI(50) = 0.91) was found. Additionally, compounds with selectivity toward the tumor cell lines NCI-ADR/RES, OVCAR-3, and HT29 were discovered.


Assuntos
Piranos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células HT29 , Humanos , Concentração Inibidora 50 , Piranos/síntese química , Piranos/farmacologia
20.
BMC Complement Altern Med ; 11: 25, 2011 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-21429215

RESUMO

BACKGROUND: Arctium lappa, known as burdock, is widely used in popular medicine for hypertension, gout, hepatitis and other inflammatory disorders. Pharmacological studies indicated that burdock roots have hepatoprotective, anti-inflammatory, free radical scavenging and antiproliferative activities. The aim of this study was to evaluate total phenolic content, radical scavenging activity by DPPH and in vitro antiproliferative activity of different A. lappa root extracts. METHODS: Hot and room temperature dichloromethanic, ethanolic and aqueous extracts; hydroethanolic and total aqueous extract of A. lappa roots were investigated regarding radical scavenging activity by DPPH, total phenolic content by Folin-Ciocalteau method and antiproliferative in vitro activity was evaluated in human cancer cell lines. The hydroethanolic extract analyzed by high-resolution electrospray ionization mass spectroscopy. RESULTS: Higher radical scavenging activity was found for the hydroethanolic extract. The higher phenolic contents were found for the dichloromethane, obtained both by Soxhlet and maceration extraction and hydroethanolic extracts. The HRESI-MS demonstrated the presence of arctigenin, quercetin, chlorogenic acid and caffeic acid compounds, which were identified by comparison with previous data. The dichloromethane extracts were the only extracts that exhibited activity against cancer cell lines, especially for K562, MCF-7 and 786-0 cell lines. CONCLUSIONS: The hydroethanolic extracts exhibited the strongest free radical scavenging activity, while the highest phenolic content was observed in Soxhlet extraction. Moreover, the dichloromethanic extracts showed selective antiproliferative activity against K562, MCF-7 and 786-0 human cancer cell lines.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Antioxidantes/uso terapêutico , Arctium/química , Neoplasias/tratamento farmacológico , Fenóis/uso terapêutico , Fitoterapia , Extratos Vegetais/uso terapêutico , Antineoplásicos Fitogênicos/análise , Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/análise , Antioxidantes/farmacologia , Compostos de Bifenilo/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Fenóis/análise , Fenóis/farmacologia , Picratos/metabolismo , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Raízes de Plantas
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