RESUMEN
There is increasing evidence that tyrosine kinase inhibitors (TKIs) have significant blood glucose lowering effects. A 70-year old Caucasian male with liver cirrhosis Child-Pugh A, advanced hepatocellular carcinoma and diabetes had a stable glycemic control being treated with glibenclamide (3.5 mg twice daily). After the first daily dose of the TKI sorafenib (800 mg) the patient experienced acute nocturnal disorientation and somnolence with a corresponding blood glucose of 37 mg/dl. After administration of glucose intravenously the neurological disturbances were completely reversible. As there was no intercurrent deterioration neither of hepatic nor of renal function, the severe hypoglycemia can likely be attributed to a drug-drug interaction of sorafenib with the sulfonylurea. The complete inhibition of the CYP2C9 and CYP3A4 mediated metabolic pathway of glibenclamide through sorafenib might have resulted in a rapid accumulation of glibenclamide. Profound blood glucose lowering effects of sorafenib might have additionally contributed to the hypoglycemic episode.
Asunto(s)
Gliburida/efectos adversos , Hipoglucemia/inducido químicamente , Niacinamida/análogos & derivados , Compuestos de Fenilurea/efectos adversos , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Glucemia/efectos de los fármacos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Interacciones Farmacológicas , Gliburida/uso terapéutico , Humanos , Hipoglucemia/fisiopatología , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Masculino , Niacinamida/efectos adversos , Niacinamida/uso terapéutico , Compuestos de Fenilurea/uso terapéutico , Índice de Severidad de la Enfermedad , SorafenibRESUMEN
INTRODUCTION: The cytochrome P4502C enzymes account for the metabolism of approximately 20% of therapeutic drugs including certain oral antidiabetic drugs (OADs). AREAS COVERED: This review focuses on the effect of CYP2C enzymes on metabolism of sulphonylureas (SUs), meglitinides, and thiazolidinediones (TZDs) discussing their impact on pharmacokinetics, drug interactions and toxicological profiles. Pharmacogenetic aspects reflecting individual gene variants and variable drug effects are also considered. EXPERT OPINION: Genetic polymorphisms of CYP2C9 enzymes (*2/*2, *2/*3, *3/*3) influence the glycaemic response to SUs and impair their substrate metabolism. Restricted data from small-sized studies with heterogenous definitions of hypoglycaemia revealed no clear association between CYP2C9 genotypes and the risk of hypoglycaemia. Functional polymorphisms of CYP2C8- and CYP2C9 drug metabolizing genes affect markedly pharmacokinetics of meglitinides. Compared to wild-type carriers, patients treated with TZDs and carrying the common CYP2C8*3 and *4 variants showed a reduced glycaemic control. The strong CYP2C8 and OATP1B1 inhibitor gemfibrozil increases substantially the plasma concentrations of repaglinide and TZDs. Numerous metabolic drug interactions exist between SUs and commonly prescribed drugs, especially anti-infectives. The complex pharmacokinetic and pharmacogenetic properties and the unfavourable short and long term risk profile of glibenclamide and glimepiride raise the question whether their use can be justified any longer.
Asunto(s)
Sistema Enzimático del Citocromo P-450/metabolismo , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/uso terapéutico , Farmacogenética , Administración Oral , Benzamidas/efectos adversos , Benzamidas/farmacocinética , Glucemia/análisis , Carbamatos/efectos adversos , Carbamatos/farmacocinética , Sistema Enzimático del Citocromo P-450/genética , Interacciones Farmacológicas , Gemfibrozilo/efectos adversos , Gemfibrozilo/farmacocinética , Humanos , Inactivación Metabólica , Piperidinas/efectos adversos , Piperidinas/farmacocinética , Polimorfismo de Nucleótido Simple , Compuestos de Sulfonilurea/efectos adversos , Compuestos de Sulfonilurea/farmacocinética , Tiazolidinedionas/efectos adversos , Tiazolidinedionas/farmacocinéticaRESUMEN
BACKGROUND/AIMS: The role of H. pylori in the pathogenesis of ulcer disease in cirrhotic patients is poorly defined. Therefore, we sought to investigate the prevalence of H. pylori infection and the occurrence of gastroduode-nal lesions in patients with liver cirrhosis. METHODS AND PATIENTS: Seroprevalence of H. pylori was tested in 110 patients with liver cirrhosis and 44 asymptomatic patients with chronic hepatitis without cirrhosis using an anti-H. pylori-IgG-ELISA. Cirrhotic patients underwent upper intestinal endoscopy for macroscopic and histological evaluation of gastric mucosa, and for the detection of mucosal colonisation of H. pylori using Giemsa staining and urease test. RESULTS: There was no significant difference between the H. pylori seroprevalence in patients with liver cirrhosis (76/110; 69%) and patients with chronic viral hepatitis (27/44, 63%, p=0.465). Gastric mucosal colonization with H. pylori in cirrhotic patients was significantly lower than the serologically determined H. pylori prevalence (45% vs. 69%, p=0.001). Etiology of liver cirrhosis did not influence the prevalence of H. pylori infection. 8 of 110 cirrhotic patients had gastric ulcers and 10 had duodenal ulcers. 61% of cirrhotic patients with peptic ulcers were asymptomatic. H. pylori was histologically identified in 61% of gastroduodenal ulcers, and 47% of gastroduodenal erosions. CONCLUSIONS: Patients with liver cirrhosis have a high prevalence of gastroduodenal ulcers. The lack of a firm association between H. pylori prevalence and ulcer frequency in cirrhotic patients argues against a pivotal role of H. pylori in the etiology of ulcers in cirrhotic patients.
RESUMEN
Interleukin-8 (IL-8) plays a central role in the pathogenesis of Helicobacter pylori infection. We used four different H. pylori strains isolated from patients with gastritis or duodenal ulcer disease to examine their differential effects on signaling pathways and IL-8 gene response in gastric epithelial cells. IL-8 mRNA level is elevated in response to high (100) multiplicity of infection (MOI) independent of cagA, vacA, and dupA gene characteristics. By lower MOIs (1 or 10), only cagA ( + ) strains significantly induce IL-8 gene expression. This is based on differential regulation of IL-8 promoter activity. Analysis of intracellular signaling pathways indicates that H. pylori clinical isolates induce IL-8 gene transcription through NF-κB p65, but by a MOI-dependent differential activation of MAPK pathways. Thus, the major virulence factors of H. pylori CagA, VacA, and DupA might play a minor role in the level of IL-8 gene response to a high bacterial load.
Asunto(s)
Carga Bacteriana , Regulación de la Expresión Génica , Helicobacter pylori/patogenicidad , Interleucina-8/metabolismo , Transducción de Señal , Factores de Virulencia/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Línea Celular , Úlcera Duodenal/inmunología , Úlcera Duodenal/microbiología , Úlcera Duodenal/fisiopatología , Células Epiteliales/inmunología , Células Epiteliales/microbiología , Gastritis/inmunología , Gastritis/microbiología , Gastritis/fisiopatología , Infecciones por Helicobacter/inmunología , Infecciones por Helicobacter/microbiología , Helicobacter pylori/clasificación , Helicobacter pylori/genética , Helicobacter pylori/aislamiento & purificación , Humanos , Interleucina-8/genética , Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , FN-kappa B/genética , FN-kappa B/metabolismo , Regiones Promotoras Genéticas/genética , Estómago/citología , Estómago/inmunología , Estómago/microbiología , Transcripción Genética , Factores de Virulencia/genéticaAsunto(s)
Antraciclinas/aislamiento & purificación , Antibacterianos/aislamiento & purificación , Streptomyces/química , Anhídridos/química , Anhídridos/aislamiento & purificación , Anhídridos/farmacología , Antraciclinas/química , Antraciclinas/farmacología , Antibacterianos/química , Antibacterianos/farmacología , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/aislamiento & purificación , Antibióticos Antineoplásicos/farmacología , Bacillus subtilis/efectos de los fármacos , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Espectroscopía de Resonancia Magnética , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Picea/microbiología , Streptomyces/aislamiento & purificaciónRESUMEN
Piceamycin, a new macrolactam polyketide antibiotic, was detected by HPLC-diode array screening in extracts of Streptomyces sp. GB 4-2, which was isolated from the mycorrhizosphere of Norway spruce. The structure of piceamycin was determined by mass spectrometry and NMR experiments. It showed inhibitory activity against Gram-positive bacteria, selected human tumor cell lines and protein tyrosine phosphatase 1B.
Asunto(s)
Acetilcisteína/metabolismo , Antibacterianos/química , Antineoplásicos/química , Lactamas Macrocíclicas/química , Streptomyces/metabolismo , Acetilcisteína/química , Antibacterianos/metabolismo , Antibacterianos/farmacología , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Bacterias Grampositivas/efectos de los fármacos , Humanos , Lactamas Macrocíclicas/metabolismo , Lactamas Macrocíclicas/farmacología , Pruebas de Sensibilidad Microbiana , Micorrizas/metabolismo , Picea/microbiología , Raíces de Plantas/microbiología , Proteína Tirosina Fosfatasa no Receptora Tipo 1/antagonistas & inhibidores , Proteínas Recombinantes/antagonistas & inhibidores , Streptomyces/crecimiento & desarrolloRESUMEN
The proximicins A-C (1-3) are novel naturally occurring gamma-peptides with a hitherto unknown 2,4-disubstituted furan amino acid as a core structure. They show a moderate cytotoxic activity and induce upregulation of cell cycle regulating proteins (p53 and p21) and lead to cell cycle arrest in G0/G1-phase. Hybrid molecules combining structural motifs of the proximicins and of netropsin (4), a structurally related natural product, seem to have similar effects. Herein we describe the synthesis of a netropsin-proximicin-hybrid library and its evaluation regarding cytotoxicity and minor groove binding activity.
Asunto(s)
Antineoplásicos/síntesis química , ADN/metabolismo , Netropsina/análogos & derivados , Antineoplásicos/química , Antineoplásicos/toxicidad , Línea Celular Tumoral , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , ADN/química , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Netropsina/síntesis química , Netropsina/toxicidad , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
BACKGROUND: Type 2 diabetes is progressive in nature and so to control cardiovascular risk, most patients need combinations of oral antidiabetic drugs (OADs) plus or minus insulin. Thus, drug-drug interactions may substantially contribute to harmful effects of intensive glucose lowering therapy. METHODS: A PubMed literature search was performed to select the most recent and relevant publications examining OAD metabolism and the effects of concomitant use of OADs. RESULTS/CONCLUSION: Considering the individual sensitivity to OADs, pharmacogenetic factors could be of critical importance. The therapeutic range and efficacy as well as adverse effects of OADs may be significantly affected by genetic polymorphisms of cytochrome P450 drug metabolising enzymes, organic cation transporters or organic anion transporting polypeptides. Although current data suggest that modest pharmacokinetics interferences among some OAD combinations exist, they do not seem to have substantial clinical consequences. As long-term adherence to multi-drug treatment is poor in diabetic patients, the future will show a strong move towards earlier treatment with combination therapies. As metformin is cardiovascular protective and is not metabolised through the hepatic cytochrome P450 system, it is a key compound for any OAD combination. There is an overwhelming amount of small-sized in vitro studies and investigations mostly including healthy volunteers dealing with short-term effects and surrogate parameters of concomitant OAD use. Further evidence from large-scale studies including typical subjects with type 2 diabetes, in particular multimorbid and geriatric patients with polypharmacy, is needed. Postmarketing surveillance using large patients' registries could be helpful to improve the early detection of clinically relevant drug-drug interactions.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/farmacocinética , Farmacogenética , Administración Oral , Animales , Glucemia/efectos de los fármacos , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/prevención & control , Sistema Enzimático del Citocromo P-450/genética , Sistema Enzimático del Citocromo P-450/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/genética , Interacciones Farmacológicas , Humanos , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/farmacología , Polimorfismo GenéticoRESUMEN
Caboxamycin, a new benzoxazole antibiotic, was detected by HPLC-diode array screening in extracts of the marine strain Streptomyces sp. NTK 937, which was isolated from deep-sea sediment collected in the Canary Basin. The structure of caboxamycin was determined by mass spectrometry, NMR experiments and X-ray analysis. It showed inhibitory activity against Gram-positive bacteria, selected human tumor cell lines and the enzyme phosphodiesterase.
Asunto(s)
Antibacterianos/biosíntesis , Antibacterianos/farmacología , Benzoxazoles/farmacología , Streptomyces/metabolismo , Antibacterianos/aislamiento & purificación , Antibióticos Antineoplásicos/farmacología , Benzoxazoles/aislamiento & purificación , Benzoxazoles/metabolismo , Línea Celular Tumoral , Supervivencia Celular , Evaluación Preclínica de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Fermentación , Bacterias Grampositivas/efectos de los fármacos , Humanos , Espectroscopía de Resonancia Magnética , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Conformación Molecular , Agua de Mar/microbiología , Espectrometría de Masa por Ionización de Electrospray , Espectrofotometría Infrarroja , Espectrofotometría Ultravioleta , Streptomyces/química , Microbiología del AguaRESUMEN
A family of three novel aminofuran antibiotics named as proximicins was isolated from the marine Verrucosispora strain MG-37. Proximicin A was detected in parallel in the marine abyssomicin producer "Verrucosispora maris" AB-18-032. The characteristic structural element of proximicins is 4-amino-furan-2-carboxylic acid, a hitherto unknown gamma-amino acid. Proximicins show a weak antibacterial activity but a strong cytostatic effect to various human tumor cell lines.
Asunto(s)
Actinobacteria/metabolismo , Antibacterianos/farmacología , Antibióticos Antineoplásicos/farmacología , Netropsina/análogos & derivados , Actinobacteria/química , Actinobacteria/clasificación , Antibacterianos/biosíntesis , Antibacterianos/aislamiento & purificación , Antibióticos Antineoplásicos/biosíntesis , Antibióticos Antineoplásicos/aislamiento & purificación , Bacterias/efectos de los fármacos , Línea Celular Tumoral , Fenómenos Químicos , Química Física , Cromatografía Líquida de Alta Presión , Fermentación , Humanos , Pruebas de Sensibilidad Microbiana , Netropsina/biosíntesis , Netropsina/aislamiento & purificación , Netropsina/farmacología , Espectrofotometría UltravioletaRESUMEN
BACKGROUND & AIMS: K(+) recycling at the apical membrane of gastric parietal cells is a prerequisite for gastric acid secretion. Two K(+) channels are currently being considered for this function, namely KCNQ1 and inwardly rectifying K(+) channels (Kir). This study addresses the subcellular localization, trafficking, and potential functional significance of KCNQ1 and Kir4.1 channels during stimulated acid secretion. METHODS: The effect of pharmacologic KCNQ1 blockade on acid secretion was studied in cultured rat and rabbit parietal cells and in isolated mouse gastric mucosa. The subcellular localization of KCNQ1 and Kir4.1 was determined in highly purified membrane fractions by Western blot analysis as well as in fixed and living cells by confocal microscopy. RESULTS: In cultured parietal cells and in isolated gastric mucosa, a robust acid secretory response was seen after complete pharmacologic blockade of KCNQ1. Both biochemical and morphologic data demonstrate that Kir4.1 and KCNQ1 colocalize with the H(+)/K(+)-ATPase but do so in different tubulovesicular pools. All Kir4.1 translocates to the apical membrane after stimulation in contrast to only a fraction of KCNQ1, which mostly remains cytoplasmic. CONCLUSIONS: Acid secretion can be stimulated after complete pharmacologic blockade of KCNQ1 activity, suggesting that additional apical K(+) channels regulate gastric acid secretion. The close association of Kir4.1 channels with H(+)/K(+)-ATPase in the resting and stimulated membrane suggests a possible role for Kir4.1 channels during the acid secretory cycle.
Asunto(s)
Ácido Gástrico/metabolismo , Canal de Potasio KCNQ1/metabolismo , Células Parietales Gástricas/metabolismo , Canales de Potasio de Rectificación Interna/metabolismo , Animales , Western Blotting , Células Cultivadas , Cromanos/farmacología , Modelos Animales de Enfermedad , ATPasa Intercambiadora de Hidrógeno-Potásio/metabolismo , Inmunohistoquímica , Inmunoprecipitación , Canal de Potasio KCNQ1/antagonistas & inhibidores , Masculino , Ratones , Microscopía Confocal , Células Parietales Gástricas/citología , Células Parietales Gástricas/efectos de los fármacos , Canales de Potasio de Rectificación Interna/antagonistas & inhibidores , Conejos , Ratas , Ratas Wistar , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Sulfonamidas/farmacologíaRESUMEN
The emergence of antibiotic resistant H. pylori strains has necessitated the identification of alternative additive therapies for the treatment of this infection. The study tested whether a specific pine bark extract (Pycnogenol is effective in inhibiting the growth and adherence of H. pylori in vitro. Inhibition of H. pylori growth by Pycnogenol was tested in liquid medium as well as in an in vitro model by using sessile bacteria attached to AGS cells. Adherence was determined by co-incubation of gastric cells with Pycnogenol and H. pylori in vitro. Pycnogenol inhibited H. pylori growth in suspension with an MIC(50) of 12.5 microg/mL. Growth of H. pylori in infected cells was reduced to 10% of the control value by 125 microg/mL Pycnogenol. Adherence of H. pylori to gastric cells was reduced by 70% after 3 h incubation with 125 microg/mL Pycnogenol. The results show a significant, yet limited inhibition of growth and adherence of H. pylori to gastric cells by Pycnogenol. In vivo studies have to demonstrate the clinical relevance of these findings.
Asunto(s)
Adhesión Bacteriana/efectos de los fármacos , Flavonoides/farmacología , Mucosa Gástrica/microbiología , Helicobacter pylori/efectos de los fármacos , Línea Celular , Mucosa Gástrica/citología , Helicobacter pylori/crecimiento & desarrollo , Humanos , Pruebas de Sensibilidad Microbiana , Extractos VegetalesAsunto(s)
Antineoplásicos/farmacología , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Netropsina/análogos & derivados , Netropsina/farmacología , Proteína p53 Supresora de Tumor/genética , Regulación hacia Arriba/efectos de los fármacos , Actinobacteria/química , Furanos , Estructura Molecular , Netropsina/química , Netropsina/aislamiento & purificaciónRESUMEN
Induction of apoptosis by the PP1/PP2A inhibitor calyculin A was inhibited if the CaMKII inhibitor KN-93 was added no later than 10 min after addition of calyculin A. The physiological relevance and mechanism of CaMKII during apoptosis, however, remains largely unclear. Here we show in MDCK and gastric parietal cells that normal transregulation of CaMKII terminates the initial burst of autophosphorylation after only 10 min. The kinetics of CaMKII involved transregulation by PP1, PP2A, PP2B and PKCalpha. Transregulation of CaMKII resulted in two kinetic phases for phosphorylation of the autoactivation site at T286/287. During the initial phase, there was a clear peak of phosphorylation that lasted 10 min. This phase was subsequently followed by a half but constant level of T286/287 phosphorylation. Calyculin A perturbed this transregulation, resulting in a hyperphosphorylated CaMKII. This effect of CA on the kinetics of CaMKII was observed in vivo as well as in vitro using isolated tubulovesicles. Calyculin A-induced hyperphosphorylation of CaMKII appears to be at least one mechanism used by cells to trigger apoptosis. Therefore, stringent limitation of CaMKII autophosphorylation at T286/287 by transregulation and prevention of hyperphosphorylation seems to restrict apoptosis.
Asunto(s)
Apoptosis , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Animales , Bencilaminas/farmacología , Línea Celular , Forma de la Célula/efectos de los fármacos , Perros , Inhibidores Enzimáticos/farmacología , Membranas Intracelulares/efectos de los fármacos , Membranas Intracelulares/enzimología , Cinética , Masculino , Toxinas Marinas , Ratones , Proteínas Mutantes/metabolismo , Oxazoles/farmacología , Fosforilación/efectos de los fármacos , Ratas , Ratas Wistar , Sulfonamidas/farmacología , Factores de TiempoRESUMEN
The new benzoxazole derivative nataxazole was isolated from Streptomyces sp. (strain Tü 6176). Nataxazole is related in structure to the potent antitumor compounds UK-1 and AJI9561 and showed similar strong growth inhibitory activity against various human tumor cell lines.
Asunto(s)
Antineoplásicos/farmacología , Benzoxazoles/farmacología , Streptomyces/metabolismo , Antineoplásicos/aislamiento & purificación , Benzoxazoles/química , Benzoxazoles/aislamiento & purificación , Línea Celular Tumoral , Humanos , Estructura Molecular , Streptomyces/químicaRESUMEN
Selective inhibition of proinflammatory chemokines such as IL-8 is an important approach to combat inflammatory and infection diseases. Previous studies suggested that interaction of transcription factors NFkappaB repressing factor (NRF) and NFkappaB play a crucial role in activation of IL-8 gene expression. In a search for a specific inhibitor of IL-8 expression, we applied tandem affinity purification to investigate interaction of NRF and NFkappaB p65 in cells. We identified a synthetic peptide corresponding to aa 223-238 of NRF interfering with binding of endogenous p65 to NRF. Furthermore, nucleofection experiments were established to introduce this inhibitory peptide into the nucleus of IL-1 stimulated human cervical and Helicobacter pylori infected gastric epithelial cells. Our data clearly show that the specific peptide disturbing NRF/NFkappaB interaction is able to significantly decrease endogenous IL-8 gene transcription in response to IL-1 or Helicobacter pylori infection. Thus, our study provides novel insights into NRF and NFkappaB interaction in vivo and may facilitate the design of new anti-IL-8 drugs based on novel strategies.
Asunto(s)
Proteínas de Unión al ADN/antagonistas & inhibidores , Helicobacter pylori/inmunología , Interleucina-1/farmacología , Interleucina-8/genética , FN-kappa B/antagonistas & inhibidores , Péptidos/farmacología , Proteínas Represoras/antagonistas & inhibidores , Línea Celular Tumoral , Proteínas de Unión al ADN/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/inmunología , Células Epiteliales/microbiología , Perfilación de la Expresión Génica , Células HeLa , Infecciones por Helicobacter/inmunología , Infecciones por Helicobacter/microbiología , Helicobacter pylori/efectos de los fármacos , Humanos , Interleucina-8/antagonistas & inhibidores , Interleucina-8/metabolismo , FN-kappa B/metabolismo , Unión Proteica , Proteínas Represoras/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transcripción Genética/efectos de los fármacos , Transcripción Genética/inmunologíaRESUMEN
An actinomycete, strain Acta 3026, isolated from mangrove soil was characterized and found to belong to the genus Nocardia. The strain produces two new cytotoxic metabolites, nocardichelins A (1) and B (2). Each of the compounds strongly inhibited human cell lines from gastric adenocarcinoma, breast carcinoma, and hepatocellular carcinoma with GI50 values in a low micromolar to nanomolar range. The structural characterization of the compounds was performed by mass spectrometry and NMR spectroscopy. The nocardichelins represent a new group of siderophores that combine the structural elements of mycobactin-type siderophores from mycobacteria and hydroxamate-type siderophores (desferrioxamine B) produced by streptomycetes. The chromazurol S assay, characteristic for iron(III) complexation, was positive, confirming the role as a siderophore.
Asunto(s)
Antineoplásicos/aislamiento & purificación , Ácidos Grasos/aislamiento & purificación , Nocardia/química , Sideróforos/aislamiento & purificación , Aminoácidos/análisis , Antineoplásicos/química , Antineoplásicos/farmacología , Deferoxamina/química , Ensayos de Selección de Medicamentos Antitumorales , Ácidos Grasos/análisis , Ácidos Grasos/química , Ácidos Grasos/farmacología , Humanos , Hierro/metabolismo , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Nocardia/genética , Resonancia Magnética Nuclear Biomolecular , ARN Ribosómico 16S/genética , Sideróforos/química , Sideróforos/farmacologíaRESUMEN
Two new aminophenoxazinone compounds with antitumor activity, elloxazinone A and B, were isolated from the culture filtrate of Streptomyces griseus Acta 2871. Their chemical structures were determined by mass spectrometry, NMR spectroscopy and X-ray analysis. Elloxazinones A and B showed a moderate inhibition of the proliferation of human cells from gastric adenocarcinoma in vitro but a strong inhibition of hepatocellular carcinoma cells whereas elloxazinone B strongly inhibited the proliferation of human breast carcinoma cells.
Asunto(s)
Antibióticos Antineoplásicos/aislamiento & purificación , Oxazinas/aislamiento & purificación , Streptomyces griseus/metabolismo , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacología , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Fermentación , Humanos , Espectroscopía de Resonancia Magnética , Oxazinas/química , Oxazinas/farmacología , Streptomyces griseus/clasificación , Relación Estructura-ActividadRESUMEN
Three new members of the fluostatin family, fluostatins C-E, were discovered in a culture filtrate extract of strain Acta 1383 during an HPLC screening program. The producing strain belongs to the genus Streptomyces and is closely related to type strains classified in the Streptomyces lavendulae 16S rRNA subclade. Fluostatins are named by their characteristic fluorenone chromophore. Fluostatin C shows moderate activity against selected human tumor cell lines.
Asunto(s)
Antineoplásicos/aislamiento & purificación , Fluorenos/aislamiento & purificación , Streptomyces/química , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Fluorenos/química , Fluorenos/farmacología , Humanos , Estructura Molecular , Espectrometría de Masa por Ionización de Electrospray , Espectrofotometría UltravioletaRESUMEN
The addition of anthranilic acid to the culture medium of the marine derived Halomonas sp. strain GWS-BW-H8hM completely altered the secondary metabolite pattern relative to the standard conditions. The red-orange color of the culture filtrate extract was the result of the production of 2-aminophenoxazin-3-one (1), chandrananimycin C (5) and three new derivatives of 1 with a previously unknown substitution pattern: 2-amino-, 2-amino-8-benzoyl-, and 2-amino-8-(4-hydroxybenzoyl)-6-hydroxyphenoxazin-3-one (2-4). The compounds were determined to have antibacterial and cytotoxic activities; a mode of action other than DNA intercalation is discussed.