RESUMEN
Lonchocarpol A, a flavanone, demonstrates in vitro inhibitory activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. This activity is antagonized by mouse plasma, which may account for its lack of in vivo activity. This compound demonstrates no differentiation with respect to the inhibition of RNA, DNA, cell wall, and protein synthesis.
Asunto(s)
Antibacterianos/farmacología , Isoflavonas/farmacología , Animales , Antibacterianos/aislamiento & purificación , Bacillus megaterium/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Enterococcus faecium/efectos de los fármacos , Isoflavonas/aislamiento & purificación , Leucemia L1210/patología , Ratones , Pruebas de Sensibilidad Microbiana , Mariposas Nocturnas/química , Mycobacterium/efectos de los fármacos , Staphylococcus aureus/efectos de los fármacos , Células Tumorales CultivadasRESUMEN
Study of surface representations of the inhibitor-bound thrombin P-1 pocket revealed a lipophilic recess in this pocket which is not occupied by any known inhibitor. Solid-phase synthesis was used to generate benzylamides of D-diphenylAlaPro by aminolysis of Boc dipeptide Kaiser resin. The resulting amides inhibited thrombin in the range IC50 = 3-13,000 nM, and the structure-activity relationships and molecular modeling suggest a unique fit of the benzyl side chain into P-1 with the meta substituent occupying the recess.
Asunto(s)
Antitrombinas/síntesis química , Compuestos de Bencidrilo/síntesis química , Pirroles/síntesis química , Trombina/antagonistas & inhibidores , Antitrombinas/química , Compuestos de Bencidrilo/química , Diseño de Fármacos , Modelos Moleculares , Pirroles/química , Relación Estructura-ActividadRESUMEN
Osteoblasts and adipocytes originate from common mesenchymal precursors. With aging, there is a decrease in osteoprogenitor cells that parallels an increase of adipocytes in bone marrow. We observed that rabbit serum (RS) induces adipocyte-like differentiation in human osteosarcoma SaOS-2/B10 and MG-63 cell lines, in rat ROS17/2.8 cells, and in mouse calvaria-derived osteoblastic MB1.8 cells, as evidenced by the accumulation of Oil Red O positive lipid vesicles and the decrease in alkaline phosphatase expression. Both SaOS-2/B10 and MG-63 cells, but not ROS17/2.8 nor MB1.8 cells, express significant levels of PPARgamma mRNA, a member of the peroxisome proliferator activated receptor (PPAR) family that has been implicated in the control of adipocyte differentiation. However, both ROS17/2.8 and MG-63 cells express significant levels of the adipocyte selective marker, aP2 fatty acid binding mRNA, which can be further increased by RS. These cell types express PPARdelta/NUC-1 but not PPARalpha, indicating that cells that do not express either PPARgamma or PPARalpha are capable of differentiating into adipocyte-like cells. Transfection experiments in COS cells showed that compared with fetal bovine serum (FBS), RS is rich in agents that stimulate PPAR-dependent transcription. The stimulatory activity was ethyl acetate extractable and was 35-fold more abundant in RS than in FBS. Purification and analysis revealed that the major components of this extract are free fatty acids. Furthermore, the same fatty acids, a mixture of palmitic, oleic, and linoleic acids, activate the PPARs and induce adipocyte-like differentiation of both ROS17/2.8 and SaOS-2/B10 cells. These findings suggest that fatty acids or their metabolites can initiate the switch from osteoblasts to adipocyte-like cells.
Asunto(s)
Adipocitos/citología , Ácidos Grasos/sangre , Osteoblastos/citología , Adipocitos/efectos de los fármacos , Animales , Diferenciación Celular/efectos de los fármacos , Línea Celular , Ácidos Grasos/aislamiento & purificación , Ácidos Grasos/fisiología , Sangre Fetal/fisiología , Humanos , Ratones , Proteínas Nucleares/fisiología , Osteoblastos/efectos de los fármacos , Conejos , Ratas , Receptores Citoplasmáticos y Nucleares/fisiología , Transactivadores/fisiología , Factores de Transcripción/fisiología , Transcripción Genética , Células Tumorales CultivadasRESUMEN
The nuclear hormone receptors NUC-1 (PPAR delta) and PPAR alpha are members of the peroxisome proliferator-activated receptor (PPAR) family. The members of this receptor family are activated by agents that stimulate peroxisome proliferation, free fatty acids, prostaglandin 12 metabolites, and agents considered for the therapy of insulin-independent diabetes mellitus. To identify putative physiological agents that activate NUC-1, we tested the ability of acetone extracts of various rat tissues to activate the transcription of an MMTV-luciferase reporter gene, via a GR/NUC-1 hybrid receptor. GR/NUC-1 contains the ligand binding region of the NUC-1 receptor and the DNA binding domain of the glucocorticoid receptor. Using this assay, we found stimulatory activity in the pancreas, which upon purification and characterization was identified as methyl-palmitate, known to be enriched in pancreatic lipids. In addition, we determined that ethyl esters of palmitic and oleic acids are also potent activators of this receptor. Thus, fatty acid ester formation may control the cellular concentrations of fatty acids, and acyl-ester formation may play a role in the control of metabolic pathways and the activation of the PPAR.
Asunto(s)
Ácidos Grasos/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Factores de Transcripción/metabolismo , Animales , Ácidos Grasos/farmacología , Femenino , Genes Reporteros , Técnicas In Vitro , Luciferasas/genética , Palmitatos/metabolismo , Palmitatos/farmacología , Páncreas/metabolismo , Embarazo , Ratas , Receptores Citoplasmáticos y Nucleares/efectos de los fármacos , Receptores Citoplasmáticos y Nucleares/genética , Factores de Transcripción/efectos de los fármacos , Factores de Transcripción/genética , Transcripción Genética/efectos de los fármacosRESUMEN
Bioactivity-directed fractionation, using brine shrimp lethality and murine hypoglycemia, of an ethanol extract prepared from Tillandsia usneoides, led to the isolation of four apparently bioactive compounds from the water-soluble fraction. The compounds were identified as citric acid, succinic acid, 3-hydroxy-3-methylglutaric acid (HMG), and 3,6,3',5'-tetramethoxy-5,7,4'-trihydroxyflavone-7-O-beta-D-g lucoside. The brine shrimp lethality of the acids was simply due to acidity; however, HMG elicited significant hypoglycemic responses in fasting normal mice. Ethyl and methyl esters of citric acid were prepared and tested in the murine hypoglycemic assay. Five of the predominant sugars were identified by tlc. Free thymidine was also isolated. Further evaluation of HMG and other potential inhibitors of HMG CoA lyase, in the treatment of symptoms of diabetes mellitus, is suggested.
Asunto(s)
Hipoglucemiantes/química , Meglutol/química , Plantas Medicinales/química , Animales , Artemia , Glucemia/metabolismo , Cromatografía en Capa Delgada , Hipoglucemiantes/farmacología , Hipoglucemiantes/toxicidad , Dosificación Letal Mediana , Louisiana , Espectroscopía de Resonancia Magnética , Masculino , Espectrometría de Masas , Meglutol/farmacología , Meglutol/toxicidad , Ratones , Espectrofotometría InfrarrojaRESUMEN
A preliminary characterization is provided of a naturally occurring cyclic peptide with interesting and potent biological activity. A 31-residue cyclic peptide, designated cyclopsychotride A [1], was obtained from the organic extract of the tropical plant, Psychotria longipes. Compound 1 inhibited [125I] neurotensin (NT) binding to HT-29 cell membranes (IC50 3 microM) and also stimulated increased levels of cytosolic Ca2+ in two unrelated cell lines that do not express NT receptors. The peptide was found to dose-dependently increase intracellular Ca2+ at concentrations ranging from 3 to 30 microM, and this response was not blocked by a known NT antagonist. Cyclopsychotride A [1] possesses three disulfide linkages and is thought to be the largest cyclic peptide isolated from a natural source. Both 1H-nmr and cd spectroscopy showed 1 to be highly structured.
Asunto(s)
Ciclotidas , Neurotensina/antagonistas & inhibidores , Péptidos Cíclicos/aislamiento & purificación , Plantas Medicinales/química , Secuencia de Aminoácidos , Brasil , Calcio/metabolismo , Dicroismo Circular , Humanos , Espectroscopía de Resonancia Magnética , Datos de Secuencia Molecular , Péptidos Cíclicos/farmacología , Conformación Proteica , Espectrometría de Masa Bombardeada por Átomos Veloces , Células Tumorales CultivadasRESUMEN
The 1H- and 13C-nmr spectra of taxol [1], 7-epi-taxol [2], and cephalomannine [3] were assigned using modern 1D and 2D nmr methods. Preliminary conformational information was obtained by nOe spectroscopy.
Asunto(s)
Alcaloides/química , Antineoplásicos Fitogénicos/química , Taxoides , Espectroscopía de Resonancia Magnética , PaclitaxelRESUMEN
New sources for the antitumor natural product taxol [1] are needed as demands for this promising cancer chemotherapeutic agent increase. Presently, supplies of taxol for clinical studies are obtained from the bark of Taxus brevifolia, a potentially limited source. Using analytical methods, the needles and stems of six Taxus species have been examined for taxol [1] and 10-deacetylbaccatin III [5], a related compound that can be converted to taxol through a semi-synthetic route. Amounts of taxol comparable to quantities reported from the bark of T. brevifolia were found in the needles of four of the Taxus species investigated. In addition, taxol was isolated from the needles of one Taxus species. Thus, Taxus needles may provide a renewable source of this valuable compound.