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1.
Bioorg Chem ; 91: 103139, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31369976

RESUMO

The facile synthesis of water-soluble mitochondria targeting thioglycosylated BODIPYs is reported. Thioglycosylated BODIPYs were synthesized in 25-26% yields via thioglycosylated dipyrromethanes in four steps. The dipyrromethanes and thioglycosylated BODIPYs were characterized by various techniques including HRMS, NMR spectroscopy and X-ray crystallography. In-vitro cellular investigations in skin keratinocyte (HaCaT) and cervical (HeLa) cancer cells revealed significant cytotoxicities with IC50 values between 23.83 to 48.61 µM. The flow cytometry experiments revealed significant cellular uptake of thioglycosylated BODIPYs into HaCaT cells and thioglucosyl substituted BODIPY (9) showed higher cellular uptake and ROS generation than the rest of the molecules. The highlight of this study is the mitochondrial targeting by the neutral BODIPYs, as judged by the colocalization experiments using confocal microscopy.


Assuntos
Antineoplásicos/farmacologia , Compostos de Boro/farmacologia , Corantes Fluorescentes/farmacologia , Mitocôndrias/metabolismo , Tioglicosídeos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Compostos de Boro/síntese química , Compostos de Boro/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/toxicidade , Células HeLa , Humanos , Mitocôndrias/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Solubilidade , Nanomedicina Teranóstica/métodos , Tioglicosídeos/síntese química , Tioglicosídeos/toxicidade , Água/química
2.
Artigo em Inglês | MEDLINE | ID: mdl-30961430

RESUMO

This study reports a novel and efficient method for the synthesis of the first reported novel class of pyrazole thioglycosides 6a-h. These series of compounds were designed through the reaction of sodium 2-cyano-3-oxo-3-(4-substitutedphenylamino)prop-1-ene-1,1-bis(thiolate) salts 2 with hydrazine hydrate in ethanol at room temperature to give the corresponding sodium 5-amino-4-(substitutedphenylcarbamoyl)-1H-pyrazole-3-thiolates 3a-d. The latter compounds were treated with protected α-D-gluco- and galacto-pyranosyl bromides 4a,b in DMF at ambient temperature to give in a high yields the corresponding pyrazole thioglycosides 6a-h. Treatment of pyrazole salts 3a-d with hydrochloric acid at amobient temperature afforded the corresponding 3-mercaptopyrazole derivatives 5. The latter compounds were treated with peracetylated sugars 4 in sodium hydride in ethanol at ambient temperature to tolerate the S-glycosyl 6a-h compounds. Ammonolysis of the pyrazole thioglycosides 6a-h afforded the corresponding free thioglycosides 7a-h. The toxicity and antitumor activities of the synthesized compounds were studied.


Assuntos
Antioxidantes/síntese química , Pirazóis/síntese química , Ribonucleosídeos/química , Tioglicosídeos/síntese química , Amidas , Animais , Antioxidantes/farmacologia , Antioxidantes/toxicidade , Desenho de Fármacos , Masculino , Camundongos , Estrutura Molecular , Pirazóis/farmacologia , Pirazóis/toxicidade , Ribose , Relação Estrutura-Atividade , Tioglicosídeos/farmacologia , Tioglicosídeos/toxicidade
3.
Artigo em Inglês | MEDLINE | ID: mdl-26462063

RESUMO

The reaction of sodium 2,2-dicyanoethene-1,1-bis(thiolate) with 2-cyano-N-arylacetamides afforded sodium pyridine-4-thiolates, coupling of the latters with 2,3,4,6-tetra-O-acetyl-D-gluco- and D-galactopyranosyl bromides, respectively, afforded new pyridine-4-thioglycosides. Ammonolysis of the latter compounds afforded the free thioglycosides. The antitumor activities of the synthesized compounds were tested against human tumor cell lines; lung (A549), colon (HCT116), liver (HEPG2), and prostate (PC3).


Assuntos
Antineoplásicos/síntese química , Piridinas/síntese química , Tioglicosídeos/síntese química , Tionucleosídeos/síntese química , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Desenho de Fármacos , Humanos , Masculino , Piridinas/toxicidade , Tioglicosídeos/toxicidade , Tionucleosídeos/toxicidade
4.
Biochemistry ; 43(34): 10918-29, 2004 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-15323552

RESUMO

Since the role of saccharides in cell recognition, metabolism, and cell labeling is well-established, the conjugation of saccharides to drugs is an active area of research. Thus, one goal in the use of saccharide-drug conjugates is to impart a greater specificity toward a given cell type or other targets. Although widely used to treat some cancers and age related macular degeneration, the drugs used in photodynamic therapy (PDT) display poor chemical selectivity toward the intended targets, and uptake by cells most likely arises from passive, diffusional processes. Instead, the specific irradiation of the target tissues, and the formation of the toxic species in situ, are the primary factors that modulate the selectivity in the present mode of PDT. We report herein a two-step method to make nonhydrolyzable saccharide-porphyrin conjugates in high yields using a tetra(pentafluorophenyl)porphyrin and the thio derivative of the sugar. As a demonstration of their properties, the selective uptake (and/or binding) of these compounds to several cancer cell types was examined, followed by an investigation of their photodynamic properties. As expected, different malignant cell types take up one type of saccharide-porphyrin conjugate preferentially over others; for example, human breast cancer cells (MDA-MB-231) absorb a tetraglucose-porphyrin conjugate over the corresponding galactose derivative. Doseametric studies reveal that these saccharide-porphyrin conjugates exhibit varying PDT responses depending on drug concentration and irradiation energy. (1) Using 20 microM conjugate and greater irradiation energy induces cell death by necrosis. (2) When 10-20 microM conjugate and less irradiation energy are used, both necrosis and apoptosis are observed. (3) Using 10 microM and the least irradiation energy, a significant reduction in cell migration is observed, which indicates a reduction in aggressiveness of the cancer cells.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Sistemas de Liberação de Medicamentos , Fotoquimioterapia/métodos , Porfirinas/síntese química , Tioglicosídeos/síntese química , Animais , Apoptose/efeitos dos fármacos , Sítios de Ligação , Neoplasias da Mama/tratamento farmacológico , Proteína Tirosina Quinase CSK , Linhagem Celular Transformada , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Fibroblastos/efeitos dos fármacos , Fibroblastos/enzimologia , Fibroblastos/metabolismo , Glicosilação , Humanos , Proteína Oncogênica pp60(v-src)/biossíntese , Proteína Oncogênica pp60(v-src)/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Porfirinas/metabolismo , Porfirinas/toxicidade , Proteínas Tirosina Quinases/biossíntese , Proteínas Tirosina Quinases/genética , Ratos , Tioglicosídeos/metabolismo , Tioglicosídeos/toxicidade , Quinases da Família src
5.
Xenobiotica ; 20(2): 223-30, 1990 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-2110394

RESUMO

1. Glucosinolate-rich diet (RM) in growing rats increased liver (a), kidneys (b), and thyroid (c) weights and depleted feed intake (d), growth curve (e) and T4 and T3 plasma levels (f). 2. Oral administration of phenobarbital enhanced the toxic effect of RM on (b), (d) and (e) and did not modify the toxic effect of RM on (a), (c) and (f). 3. RM had a depleting effect on hepatic microsomal P-450 specific activity. 4. RM had an enhancing effect on hepatic glutathione S-transferase and UDP-glucuronyltransferase specific activities. 5. These results indicate that some glucosinolate derivatives released by gut microflora metabolism are further metabolized by the hepatic detoxification system, and that they could play the role of co-toxic or co-detoxic molecules.


Assuntos
Dieta , Glucosinolatos/toxicidade , Microssomos Hepáticos/enzimologia , Tioglicosídeos/toxicidade , Animais , Brassica , Sistema Enzimático do Citocromo P-450/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Glucosinolatos/administração & dosagem , Glucosinolatos/farmacologia , Glucuronosiltransferase/metabolismo , Glutationa Transferase/metabolismo , Inativação Metabólica , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Tamanho do Órgão/efeitos dos fármacos , Fenobarbital/farmacologia , Ratos , Glycine max , Tiroxina/sangue , Tri-Iodotironina/sangue , Aumento de Peso/efeitos dos fármacos
6.
Res Vet Sci ; 43(3): 313-9, 1987 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-3444977

RESUMO

Glucosinolates were removed from whole rapeseed by a hot-water extraction procedure or depleted by heat treatment. When laying hens were maintained for three months on diets containing about 300 g kg-1 of these rapeseed cakes, the incidence of liver haemorrhages detected at post mortem examination was similar to that in birds maintained on 300 g kg-1 commercial rapeseed meal and significantly greater than in control birds fed soya-based diets. The effectiveness of glucosinolate extraction or depletion was determined by chemical analysis and by histological examination of the thyroid glands. Histologically the haemorrhages were similar after feeding extracted and commercial rapeseed meals. Diets containing mixtures of nitriles and glucosinolates severely depressed food intake and egg production but did not cause a greater incidence of haemorrhages than the other rapeseed products tested. Mortality from causes other than liver haemorrhage was higher with the diets containing rapeseed and this suggests that rapeseed has a more generalised effect on the body's defence mechanisms. These observations suggest that other factors in rapeseed meal, alone or acting with glucosinolates, may be responsible for inducing liver haemorrhages in laying hens.


Assuntos
Ração Animal , Brassica , Galinhas , Glucosinolatos/toxicidade , Hemorragia/veterinária , Hepatopatias/veterinária , Doenças das Aves Domésticas/induzido quimicamente , Tioglicosídeos/toxicidade , Animais , Doença Hepática Induzida por Substâncias e Drogas , Feminino , Hemorragia/induzido quimicamente , Hemorragia/patologia , Hepatopatias/patologia , Doenças das Aves Domésticas/patologia
7.
J Biol Chem ; 259(9): 5465-71, 1984 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-6425290

RESUMO

The growth responses of 5-deoxy-5-methylthioribose on a 5'-deoxy-5'-methylthioadenosine phosphorylase containing cell line (BW5147) and the methylthioadenosine phosphorylase-deficient cell line (L1210D) were examined. Methylthioribose was shown to dramatically affect these cells, increasing their growth rate, saturation density, and viability. It was also found that methylthioribose could satisfy the methylthio dependence of the enzyme-deficient cell line, L1210D. A model is proposed to explain the selective growth of methylthioadenosine phosphorylase-deficient cells in medium lacking a methylthio donor but containing fetal calf serum. It is hypothesized that cellularly exported methylthioadenosine is degraded to methylthioribose in the presence of medium containing serum of high methylthioadenosine phosphorylase activity (i.e. fetal calf serum). The resultant methylthioribose can then be used to satisfy the methylthio requirement of these cells. To test this theory, various purified preparations of bovine liver methylthioadenosine phosphorylase were used to artificially increase the specific activity of methylthioadenosine phosphorylase in horse serum. In each case, it was demonstrated that only medium containing serum of enzyme activity nearly equal to that of the glutathione-stimulated fetal calf serum activity, supported the growth of methylthio-dependent cells in the absence of methylthio compounds. The data suggest that the degradation of methylthioadenosine and subsequent formation of methylthioribose represents an essential process in the growth of mammalian cells.


Assuntos
Leucemia L1210/fisiopatologia , Linfoma/fisiopatologia , Pentosiltransferases/metabolismo , Purina-Núcleosídeo Fosforilase/metabolismo , Tioglicosídeos/toxicidade , Animais , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Glutationa/farmacologia , Cinética , Camundongos , Camundongos Endogâmicos AKR , Purina-Núcleosídeo Fosforilase/deficiência
10.
Science ; 200(4338): 206-7, 1978 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-635582

RESUMO

To investigate the mechanisms by which heat affects cancer cells, we used 5-thio-D-glucose, an inhibitor of glycolysis in HeLa S-3 cells, under aerobic and hypoxic conditions at temperatures ranging from 37 degrees to 43 degrees C. Drug alone or heat alone killed a minimum number of cells under aerobic or hypoxic conditions. Exposure to drug and hyperthermia selectively increased the number of cells killed under hypoxic conditions at temperatures as low as 40.5 degrees C but had little effect on cells incubated under aerobic conditions. These results suggest that the glycolytic pathways is a primary site of hyperthermic damage leading to cell death.


Assuntos
Glicólise/efeitos dos fármacos , Temperatura Alta , Neoplasias Experimentais/metabolismo , Tioglucosídeos/toxicidade , Tioglicosídeos/toxicidade , Aerobiose , Sobrevivência Celular/efeitos dos fármacos , Células HeLa , Hipóxia/metabolismo , Neoplasias Experimentais/tratamento farmacológico
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