RESUMO
A system capable of continuously measuring a range of metallic elements in the effluent gas from incinerators and other similar industrial processes, and providing on-line results has been developed. With a state-of-the-art mobile laboratory measurements were taken from a UK municipal solid waste incinerator. The detection system used was an ICP-OES, with a modified torch to allow the introduction of flue gas directly into the plasma. Metals that were investigated were Ni, Hg, V, Al, Na, Ca, Cu, Sn, Pb, Sb, As, Cd and Tl, with limits of detection in the range 0.0004 mg m(-3) to 0.1 mg m(-3) being calculated. Emission measurements produced data that showed that the MSWI plants emission were significantly lower than the emission limits specified in EC 2000/76/EC.
RESUMO
Synthesized 6-arylamino-5,8-quinolinediones 4a-4j and 6-chloro-7-arylamino-5,8-isoquinolinediones 5a-5g were evaluated for effects on NAD(P)H: quinone oxidoreductase (NQO1) activity with the cytosolic fractions derived from cultured human lung cancer cells and their cytotoxicity in cultured several human solid cancer cell lines. The 5,8-quinolinediones 4 and 5,8-isoquinolinediones 5 affected the reduction potential by NQO1 activity and showed a potent cytotoxic activity against human cancer cell lines. The tested compounds 4a, 5c, 5f, and 5g were considered as more potent cytotoxic agents. The compounds 4d, 5b, 5c, 5e and 5g were comparable modulators of NQO1 activity.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , NAD(P)H Desidrogenase (Quinona)/antagonistas & inibidores , Quinolonas/síntese química , Quinolonas/farmacologia , Quinonas/síntese química , Quinonas/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Humanos , Indicadores e ReagentesRESUMO
Nine vitamin K3 analogs were compared with respect to the induction of the cytochrome P450 1A1 (CYP1A1) expression in mouse hepatoma Hepa-1c1c7 cells. 6-(4-Diethylamino)phenyl-7-chloro-5,8-quinolinedione (EA4) caused a significant induction of the CYP1A1-mediated ethoxyresorufin O-deethylase activity in a time- and concentration-dependent manner. The induction was accompanied by an increase of the Cyp1a1 mRNA transcription. The transient expression of the mouse Cyp1a1-CAT gene into cells showed that EA4 induced CAT activity. However, the aryl hydrocarbon receptor and its nuclear partner, aryl hydrocarbon receptor nuclear translocator mRNA transcription, were unaffected by the EA4 treatment. When the cells were incubated with EA4 in the presence of 1 nM TCDD, the ethoxyresorufin O-deethylase activity that was induced by TCDD was significantly suppressed by EA4. Inhibition of protein synthesis by cycloheximide strongly enhanced the EA4-dependent Cyp1a1 mRNA expression. Up-regulation of protein kinase C by a 2 h preincubation with phorbol 12-myristate 13-acetate increased the EA4-dependent expression of the Cyp1a1 gene. In human cells, such as HepG2 (human hepatocarcinoma), MCF-7 (human breast adenocarcinoma cell line), and HL-60 (human promyelocytic cell line), the expression of CYP1A1 mRNA was also induced by EA4 treatment. Moreover, CYP1B1 mRNA was increased by EA4 in MCF-7 cells. These results indicate that EA4 modulates CYP1A1 and CYP1B1 expressions by transcriptional activation. Also, protein kinase C may be involved in the induction mechanism of CYP1A1 by EA4.
Assuntos
Hidrocarboneto de Aril Hidroxilases , Citocromo P-450 CYP1A1/genética , Proteínas de Ligação a DNA , Quinolinas/farmacologia , Vitamina K 3/análogos & derivados , Animais , Translocador Nuclear Receptor Aril Hidrocarboneto , Citocromo P-450 CYP1B1 , Sistema Enzimático do Citocromo P-450/genética , Expressão Gênica/efeitos dos fármacos , Células HL-60 , Humanos , Neoplasias Hepáticas Experimentais/enzimologia , Neoplasias Hepáticas Experimentais/genética , Camundongos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Receptores de Hidrocarboneto Arílico/genética , Acetato de Tetradecanoilforbol/farmacologia , Fatores de Transcrição/genética , Células Tumorais Cultivadas , Vitamina K 3/química , Vitamina K 3/farmacologiaRESUMO
The effects of 2-chloro-3-(4-acetophenyl)-amino-1,4-naphthoquinone (NQ301), an antithrombotic agent, on aggregation, binding of fibrinogen to glycoprotein (GP)IIb/IIIa complex and intracellular signals were investigated using human platelets. NQ301 significantly inhibited the collagen-, thrombin-, arachidonic acid-, thapsigargin- and calcium ionophore A23187-induced aggregation of washed human platelets with IC50 values of 13.0+/-0.1, 11.2+/-0.5, 21.0+/-0.9, 3.8+/-0.1 and 46.2+/-0.8 microM, respectively. NQ301 also significantly inhibited FITC-conjugated fibrinogen binding to human platelet surface GPIIb/IIIa complex, but failed to inhibit the fibrinogen binding to purified GPIIb/IIIa complex. These data demonstrate that NQ301 inhibits platelet aggregation by suppression of the intracellular pathway, rather than by direct inhibition of fibrinogen-GPIIb/IIIa complex binding. NQ301 significantly inhibited the increase of cytosolic Ca2+ concentration and ATP secretion, and also significantly increased platelet cAMP levels in the activated platelets. These results suggest that the antiplatelet activity of NQ301 may be mediated by inhibition of cytosolic Ca2+ mobilization, enhancement of cAMP production and inhibition of ATP secretion in activated platelets.
Assuntos
Plaquetas/efeitos dos fármacos , Cálcio/sangue , Naftoquinonas/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Trifosfato de Adenosina/metabolismo , Plaquetas/metabolismo , AMP Cíclico/sangue , Humanos , Técnicas In Vitro , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismoRESUMO
The effects of 2-chloro-3-(4-hexylphenyl)-amino-1,4-naphthoquinone (NQ304), an antithrombotic agent, on aggregation, binding of fibrinogen to glycoprotein IIb/IIIa and intracellular signals were investigated using human platelets. NQ304 inhibited thrombin-, arachidonic acid- and thapsigargin-induced aggregation of washed human platelets with the IC50 values of 22.2+/-0.7, 6.5+/-0.2, and 7.6+/-0.1 microM, respectively. NQ304 significantly inhibited fluorescein isothiocyanate-conjugated fibrinogen binding to human platelet surface glycoprotein IIb/IIIa receptor by 75%, but failed to inhibit the fibrinogen binding to purified glycoprotein IIb/IIIa receptor. This result suggests that NQ304 inhibit platelet aggregation by suppression of an intracellular pathway that involves exposure of the glycoprotein IIb/IIIa receptor, rather than by direct inhibition of fibrinogen-glycoprotein IIb/IIIa binding. NQ304 significantly inhibited thrombin-induced increase in intracellular Ca2+ mobilization at the dose of 30 microM and ATP secretion in a dose-dependent manner. It also inhibited thrombin- and arachidonic acid-induced thromboxane A2 formation in human platelet dose-dependently. In conclusion, the antiplatelet mechanism of NQ304 may be due to the reduction of the thromboxane A2 formation, inhibition of adenosine triphosphate release and intracellular calcium mobilization.
Assuntos
Naftoquinonas/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Ácido Araquidônico/farmacologia , Cálcio/metabolismo , Relação Dose-Resposta a Droga , Fibrinogênio/metabolismo , Fluoresceína-5-Isotiocianato/metabolismo , Humanos , Oligopeptídeos/farmacologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tapsigargina/farmacologia , Trombina/farmacologia , Tromboxano A2/biossínteseRESUMO
We have previously demonstrated that the activation of p53 signaling may contribute to tumor growth inhibition by the CRE-decoy oligonucleotide containing CRE sequence (5'-TGACGTCA-3') (Lee et al., Biochemistry 39, 4863-4868, 2000). However, growth inhibition by CRE-decoy treatment was also observed in tumor cells containing a mutant p53 (Park et al., J. Biol. Chem. 274, 1573-1580, 1999). To understand additional mechanisms of the decoy oligonucleotide, we investigated the effect on cyclin D1 expression and a cyclin D1/Cdk4/retinoblastoma protein (pRB) signaling pathway. Here we show that in MCF7 breast cancer cells the CRE-decoy competed with cyclin D1-CRE (5'-TAACGTCA-3') for binding transcription factors and reduced cyclin D1 gene expression (in reporter gene assay, Northern blotting and Western blotting) to modulate cyclin D1/Cdk4/pRB signaling and G1-S progression in a steady state and/or under estrogen stimulation. Decrease of cyclin D1 protein level by CRE-decoy treatment was also observed in p53-mutated cancer cells. Cyclin D1 expression was also diminished in MCF7 cells stably expressing dominant negative mutant CREB indicating that the nonspecific effect of oligonucleotide or its degradation products could be excluded. These data suggest that inhibition of cyclin D1 expression contributes to the growth inhibition induced by the decoy oligonucleotide in MCF7 cells through a cyclin D1/Cdk4/pRB signaling pathway. Downregulation of cyclin D1 expression also provides a mechanism of CRE-decoy-induced growth inhibition in tumor cells having p53 mutation.
Assuntos
Neoplasias da Mama/metabolismo , Ciclina D1/genética , Quinases Ciclina-Dependentes/metabolismo , Oligonucleotídeos/farmacologia , Proteínas Proto-Oncogênicas , Proteína do Retinoblastoma/metabolismo , Neoplasias da Mama/patologia , Divisão Celular/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina , Estrogênios/farmacologia , Feminino , Humanos , Regiões Promotoras Genéticas , RNA Mensageiro/biossíntese , Elementos de Resposta , Transdução de Sinais , Ativação Transcricional , Transfecção , Células Tumorais CultivadasRESUMO
The possibility of NQ12 (2-chloro-3-[4-(ethylcarboxy)-phenyl]-amino-1,4-naphthoquinone) as a novel antithrombotic agent and its mode of action were investigated. The effects of NQ12 on platelet aggregation in human platelet-rich plasma in vitro, in rats ex vivo, and on murine pulmonary thrombosis in vivo, as well as the mode of antithrombotic action were examined. NQ12 potently inhibited ADP-, collagen-, epinephrine-, and calcium ionophore-induced human platelet aggregations in vitro concentration-dependently. NQ12 significantly inhibited rat platelet aggregation in an ex vivo study. NQ12 prevented murine pulmonary thrombosis in a dose-dependent manner. However, NQ12 did not affect coagulation parameters such as activated partial thromboplastin time, prothrombin time, and thrombin time. NQ12 inhibited fibrinogen binding to the platelet surface GPIIb/IIIa receptor, but failed to inhibit binding to the purified GPIIb/IIIa receptor. Thromboxane B(2) formation caused by thrombin or collagen was inhibited significantly by NQ12. The phosphoinositide breakdown induced by thrombin or collagen was inhibited concentration-dependently by NQ12. These results suggest that NQ12 may be a promising antithrombotic agent, and its antithrombotic activity may be due to antiplatelet aggregation activity, which may result from the inhibition of phosphoinositide breakdown and thromboxane A(2) formation.
Assuntos
Fibrinolíticos/farmacologia , Naftalenos/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Animais , Coagulação Sanguínea/efeitos dos fármacos , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Modelos Animais de Doenças , Fibrinolíticos/síntese química , Fibrinolíticos/química , Fibrinolíticos/uso terapêutico , Fosfatos de Inositol/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Naftalenos/síntese química , Naftalenos/química , Naftalenos/uso terapêutico , Inibidores da Agregação Plaquetária/síntese química , Inibidores da Agregação Plaquetária/química , Inibidores da Agregação Plaquetária/uso terapêutico , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/efeitos dos fármacos , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Embolia Pulmonar/prevenção & controle , Ratos , Ratos Sprague-Dawley , Tromboxano B2/metabolismoRESUMO
5/6-Arylamino-4,7-dioxobenzothiazoles were synthesized and tested for in vitro antifungal activities against pathogenic fungi. Most of the tested 4,7-dioxobenzothiazoles exhibited potent antifungal activities against Candida species and Aspergillus niger.
Assuntos
Antifúngicos/síntese química , Aspergillus niger/efeitos dos fármacos , Candida/efeitos dos fármacos , Tiazóis/síntese química , Antifúngicos/química , Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacologia , Células Tumorais CultivadasRESUMO
Two 6-(fluorinated-phenyl)amino-5,8-quinolinedione derivatives, OQ21 and OQ1, were newly synthesized as potent inhibitors of endothelial-dependent vasorelaxation. The purpose of the present study was to investigate the effects of OQ21 and OQ1 on different types of vasorelaxation and to pursue their action mechanisms. For acetylcholine both compounds, at a low concentration (0.1 microM), reduced the maximal response with increase of EC(50) values. OQ21 is a novel quinone compound and showed a more potent and efficacious inhibitory effect on acetylcholine-induced relaxation of rat aorta than that of LY83583 (6-anilino-5,8-quinolinedione). Relatively high concentrations (1 microM) of OQ21 and OQ1 inhibited the sodium nitroprusside-induced relaxation of endothelium-denuded ring, producing rightward shifts of the curve for sodium nitroprusside without altering the maximal response. They also prevented acetylcholine and sodium nitroprusside-induced elevations of cyclic GMP. In addition, OQ21 and OQ1 (1 microM) significantly decreased (52-72%) the sensitivity of L-arginine-induced relaxation of precontracted endothelium-denuded aortic rings from lipopolysaccaride-treated (20 mg/kg, i.p.) rats. The inhibitory effect of OQ21 on endothelium-dependent vasodilation was enhanced by N(G)-nitro-L-arginine, which inhibits nitric oxide synthase (NOS) by binding the oxygenase domain of the enzyme, but not by diphenylendiodonium, which inhibits NOS by binding to the reductase domain of the enzyme. Treatment of blood vessels with OQ21 or OQ1 showed a significant increase in chemiluminescence output, which was prevented by adding superoxide dismutase, suggesting that superoxide generation is involved in the action mechanism for OQ21. Present results indicate that a novel naphthoquinone compound, OQ21, potently inhibits endothelial NOS, possibly by interacting with the reductase domain of the enzyme, which leads to induce superoxide formation. The new benzoquinone compounds, OQ21 and OQ1, inhibit not only endothelium-dependent vasorelaxation but also endothelium-independent relaxation induced by exogenous NO generated from a nitrovasodilator via the reduction of cyclic GMP. They also reduced L-arginine-induced vasorelaxation in endotoxin-treated rats, indicating their possession of inhibitory effect on inducible NOS.
Assuntos
Aminoquinolinas/farmacologia , Aorta/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Acetilcolina/farmacologia , Aminoquinolinas/química , Animais , Aorta/metabolismo , GMP Cíclico/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Inibidores Enzimáticos/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Vasodilatação/fisiologia , Vasodilatadores/farmacologiaRESUMO
The effect of p6304 (2-chloro-3-(4-hexylphenyl)-amino-1,4-naphthoquinone) as a novel antithrombotic agent was investigated. NQ304 was found to inhibit platelet aggregation in human platelets in vitro and in rat ex vivo, and murine pulmonary thrombosis in vivo. NQ304 potently inhibited adenosine diphosphate (ADP), collagen, epinephrine and calcium ionophore-induced human platelet aggregation in vitro dose-dependently. In the ex vivo study, oral administration of NQ304 significantly inhibited platelet aggregation in rats. However, NQ304 was found not to affect the coagulation system, since it did not change the prothrombin time (PT), activated partial thromboplastin time (APTT) and thrombin time (TT). The agent prevented death due to pulmonary thrombosis by the platelet aggregates in mice in vivo. In the mouse tail bleeding time test, NQ304 showed a significant prolongation of the tail bleeding time in conscious mice. These results suggest that a principal antithrombotic effect of NQ304 may be due to the antiplatelet aggregation activity but not to anticoagulation activity.
Assuntos
Fibrinolíticos/farmacologia , Naftoquinonas/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Animais , Tempo de Sangramento , Coagulação Sanguínea/efeitos dos fármacos , Plaquetas/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Técnicas In Vitro , L-Lactato Desidrogenase/sangue , Masculino , Camundongos , Camundongos Endogâmicos ICR , Agregação Plaquetária/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
5-Arylamino-2-methyl-4,7-dioxobenzothiazoles were synthesized as inhibitors of cyclin-dependent kinase 4 (CDK4) and cytotoxic agents. Most of the 4,7-dioxobenzothiazoles exhibited selective inhibitory activities for the CDK4 and cytotoxic potential against human cancer cell lines.
Assuntos
Antineoplásicos/síntese química , Quinases Ciclina-Dependentes/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Proteínas Proto-Oncogênicas , Tiazóis/síntese química , Antineoplásicos/farmacologia , Quinase 4 Dependente de Ciclina , Inibidores Enzimáticos/farmacologia , Células HL-60 , Humanos , Tiazóis/farmacologia , Células Tumorais CultivadasRESUMO
6-Arylamino-7-halo-5,8-quinolinediones (4a-4k, 5a-5b) were tested for in vitro cytotoxicity against human solid tumor cell lines such as A 549 (non-small cell lung), SK-OV-3 (ovarian), SK-MEL-2 (melanoma), HCT-15 (colon) and XF 498 (CNS) by SRB assay. The arylamino-7-chloro-5,8-quinolinediones 4 were also evaluated for cyclin-dependent kinase (CDK2 and CDK4) inhibitory effect. Among them, the 5,8-quinolinediones 4a and 5a with 7-(4-fluorophenyl)amino group were found to be potent cytotoxic against HCT 15, SKOV-3 and XF 498, and the compounds 4f and 4i showed inhibitory activities for the CDK4.
Assuntos
Antineoplásicos/farmacologia , Quinolinas/farmacologia , Antineoplásicos/síntese química , Quinases Ciclina-Dependentes/antagonistas & inibidores , Humanos , Quinolinas/síntese química , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Synthesized 5-arylamino-2-methyl-4,7-dioxobenzothiazoles 3a-3o were evaluated for modulation of NAD(P)H: quinone oxidoreductase (NQO1) activity with the cytosolic fractions derived from cultured human lung cancer cells and their cytotoxicity in cultured several human solid cancer cell lines. The 4,7-dioxobenzothiazoles affected the reduction potential by NQO1 activity and showed a potent cytotoxic activity against human cancer cell lines. The tested compounds 3a, 3b, 3g, 3h, 3n and 3o were considered as more potent cytotoxic agents, and comparable modulators of NQO1 activity.
Assuntos
Antineoplásicos/farmacologia , Equinomicina/análogos & derivados , Inibidores Enzimáticos/farmacologia , NAD(P)H Desidrogenase (Quinona)/antagonistas & inibidores , Quinona Redutases/síntese química , Tiazóis/síntese química , Antineoplásicos/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Humanos , Quinona Redutases/farmacologia , Tiazóis/farmacologia , Células Tumorais CultivadasRESUMO
Pharmacokinetics of IQO4, a new isoquinolinedione derivative, after 30-min intravenous administration of the drug, 5 mg/kg, to rats, the stability, and the blood partition between plasma and blood cells of IQO4 were evaluated. After intravenous administration, IQO4 was eliminated fast with the mean total body clearance of 105 ml/min/kg. IQO4 was almost completely metabolized in rats; 5.18% of intravenous dose of IQO4 was excreted in 24-hr urine and IQO4 was under detection limit in whole gastrointestinal tract as 24 hr. IQO4 has a good affinity to liver, small intestine, heart, lung, and kidney as reflected to greater-than-unity tissue-to-plasma ratios. IQO4 was unstable in rat whole blood, plasma, and liver homogenates when incubated in a water-bath shaker for 24 hr kept at 37 degrees C and at a rate of 50 oscillations per min. The disappearance rate constants of IQO4 were 0.0611, 0.O436, and 0.174 hr(-1) for rat whole blood, plasma, and liver homogenates, respectively. However, IQO4 was stable for up to 3-hr incubation in human gastric juices. The plasma-to-blood cell concentration ratios of IQO4 were independent of initial blood concentrations of IQO4, 0.5, 2, and 10 microg/ml, when the rabbit whole blood was incubated for up to 120 min; the ratios were in the range of 1.56-3.60. Since IQO4 was unstable in blood, considerable in vitro 'blood storage effect' in the plasma concentration of IQO4 was observed.
Assuntos
Isoquinolinas/farmacocinética , Animais , Área Sob a Curva , Estabilidade de Medicamentos , Meia-Vida , Infusões Intravenosas , Isoquinolinas/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Distribuição TecidualRESUMO
Various factors most likely to influence the plasma protein binding of IQO4, a new isoquinolinedione derivative, to 4% human serum albumin (HSA) were evaluated using an equilibrium dialysis technique at an initial IQO4 concentration of 5 microg/ml. It took approximately 12 h incubation to reach an equilibrium between 4% HSA and isotonic Sørensen phosphate buffer at pH 7.4 containing 3% dextran ('the buffer') using a Spectra/Por 2 membrane (molecular weight cut-off, 12000-14000) in a water-bath shaker kept at 37 degrees C and at a rate of 50 oscillations per min. IQO4 was stable both in 4% HSA and in 'the buffer' for up to 24 h incubation at 37 degrees C. The binding of IQO4 was constant (89.9 +/- 1.40%, mean +/- standard deviation) at IQO4 concentrations ranging from 1 to 100 microg/ml. However, the extent of binding was dependent on HSA concentrations. The values were 32.5, 62.0, 79.1, 84.9, 90.9, 91.2, and 91.7% at HSA concentrations of 0.5, 1, 2, 3, 4, 5, and 6%, respectively; on incubation temperature, 96.7, 93.8, and 91.0% when incubated at 4, 22, and 37 degrees C, respectively; and on the buffer pHs, 84.4, 87.2, 88.2, 90.9, and 92.3% for the buffer pHs of 5.8, 6.4, 7, 7.4, and 8, respectively. The free fraction of IQO4 increased with the addition of sulfisoxazole (0-300 microg/ml), and salicylic acid (0-300 microg/ml). The protein binding of IQO4 was independent of the quantity of alpha-1-acid glycoprotein (up to 0.32%), chloride ion (up to 0.546%) and heparin (up to 40 units/ml).
Assuntos
Isoquinolinas/farmacocinética , Soluções Tampão , Estabilidade de Medicamentos , Heparina/farmacologia , Humanos , Concentração de Íons de Hidrogênio , Técnicas In Vitro , Orosomucoide/metabolismo , Ligação Proteica/efeitos dos fármacos , Ácido Salicílico/farmacologia , Albumina Sérica/metabolismo , Sulfisoxazol/farmacologia , TemperaturaRESUMO
6-Arylamino-5,8-quinolinediones 3 and 7-arylamino-5,8-isoquinolinediones 4 were synthesized as inhibitors of endothelium-dependent vasorelaxation. The quinones inhibited the vasorelaxation of rat aorta with the endothelium. Among them, the quinones 3a, 3b, 3f, 4b, 4d and 4g strongly inhibited the vasorelaxation.
Assuntos
Endotélio Vascular/efeitos dos fármacos , Quinolinas/farmacologia , Animais , Aorta/efeitos dos fármacos , Aorta/fisiologia , Endotélio Vascular/fisiologia , Relaxamento Muscular/efeitos dos fármacos , Quinolinas/síntese química , Quinolinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
A high-performance liquid chromatographic method was developed for the determination of a new phospholipase A2 inhibitor, NQ12, in human plasma and urine. The sample preparation was simple: 2 volumes of acetonitrile were added to the biological samples to deproteinize it. A 50-microl aliquot of the supernatant was injected onto a C18 reversed-phase column. The mobile phase employed was 0.05M acetate buffer (pH 3) : acetonitrile : methanol (30:45:25, v/v/v) and run at a flow rate of 1.5 ml/min. The column effluent was monitored by a UV detector set at 298 nm. The retention times for NQ12 and the internal standard were approximately 5.5 and 7.0 min, respectively. The detection limits for NQ12 in human plasma and urine were all 20 ng/ml. The coefficients of variation of the assay (within-day and between-day) were generally low (below 11.8%) for human plasma and urine. No interferences from endogenous substances were found.
Assuntos
Inibidores Enzimáticos/análise , Naftalenos/análise , Cromatografia Líquida de Alta Pressão , Inibidores Enzimáticos/sangue , Inibidores Enzimáticos/urina , Humanos , Naftalenos/sangue , Naftalenos/urina , Fosfolipases A/antagonistas & inibidores , Fosfolipases A2 , Padrões de Referência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrofotometria UltravioletaRESUMO
6-Chloro-7-arylamino-5,8-isoquinolinediones were newly synthesized and evaluated for in vitro cytotoxic activities against five human solid tumor cell lines. Among them, 5b, 5c and 5d exhibited potent activities against the cell lines HCT-15 and SK-MEL-2.
Assuntos
Antineoplásicos/farmacologia , Isoquinolinas/síntese química , Isoquinolinas/farmacologia , Humanos , Concentração Inibidora 50 , Células Tumorais CultivadasRESUMO
The stability of a new phospholipase A2 inhibitor, NQ12, in various pH solutions, human plasma, urine, and gastric juices, and rat liver homogenate, the blood partition of NQ12 between plasma and blood cells of rat blood, and the factors influencing the binding of NQ12 to 4% human serum albumin (HSA) using an equilibrium dialysis technique were evaluated. NQ12 was unstable in various pH solutions, human plasma and urine, and rat liver homogenate when incubated in a water-bath shaker kept at 37 degrees C and at a rate of 50 oscillations per min. However, NQ12 was stable for up to 3-hr incubation in human gastric juice. The plasma-to-blood cell concentration ratios of NQ12 were independent of NQ12 rat blood concentrations when the whole blood was incubated for up to 2-hr; the mean (+/- standard deviation) values were 0.112 +/- 0.0650 and 0.172 +/- 0.105 at initial blood NQ12 concentrations of 10 and 20 microg/ml, respectively. The binding of NQ12 to 4% HSA was considerable (higher than 99%) at NQ12 concentrations ranging from 10 to 100 microg/ml in 4% HSA. The unbound fraction of NQ12 was dependent on NQ12 concentrations, pHs of buffer, and HSA concentrations, but was independent of the concentrations of sulfisoxazole or salicylic acid, incubation temperature, buffers containing various concentrations of chloride ion, and concentrations of heparin and alpha-1-acid glycoprotein.
Assuntos
Naftalenos/metabolismo , Naftalenos/farmacocinética , Fosfolipases A/antagonistas & inibidores , Animais , Cromatografia Líquida de Alta Pressão , Estabilidade de Medicamentos , Suco Gástrico , Humanos , Concentração de Íons de Hidrogênio , Fígado/metabolismo , Naftalenos/sangue , Naftalenos/urina , Fosfolipases A2 , Ratos , Ratos Sprague-Dawley , Albumina Sérica/metabolismoRESUMO
The antiplatelet and antithrombotic activities of a newly synthesized NQ301, 2-chloro-3-(4-acetophenyl)-amino-1,4-naphthoquinone, were investigated on human platelet aggregation in vitro and rats ex vivo, and murine pulmonary thrombosis in vivo. NQ301 potently inhibited ADP-, collagen-, epinephrine- and calcium ionophore A23187-induced human platelet aggregation in a concentration-dependent manner in vitro. NQ301 significantly inhibited platelet aggregation in orally administered rats ex vivo. NQ301 prevented death due to pulmonary thrombosis in mice dose-dependently in vivo. NQ301 also showed significant prolongation of tail bleeding time in conscious mice. However, NQ301 did not alter such coagulation parameters as activated partial thromboplastin time, prothrombin time, and thrombin time in human plasma. These results suggest that NQ301 may be a promising antithrombotic agent, and the antithrombotic activity of NQ301 may be due to antiplatelet aggregation activity but not to in vitro anticoagulation.