RESUMEN
Sacchathridine A (1) was isolated from the fermentation broth of strain Saccharothrix sp. MI559-46F5. The structure was determined as a new naphthoquinone derivative with an acetylhydrazino moiety by a combination of NMR, MS spectral analyses, and chemical degradation. Compound 1 showed inhibitory activity of prostaglandin E2 release in a concentration-dependent manner from human synovial sarcoma cells, SW982, with an IC50 value of 1.0 µM, but had no effect on cell growth up to 30 µM.
Asunto(s)
Actinomycetales/química , Dinoprostona/antagonistas & inhibidores , Naftoquinonas/aislamiento & purificación , Naftoquinonas/farmacología , Antagonistas de Prostaglandina/aislamiento & purificación , Antagonistas de Prostaglandina/farmacología , Dinoprostona/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Naftoquinonas/química , Resonancia Magnética Nuclear Biomolecular , Antagonistas de Prostaglandina/química , Sarcoma Sinovial/tratamiento farmacológicoRESUMEN
Decalpenic acid is a natural small molecule previously isolated from the fermentation broth of fungi that induces early osteoblastic markers in pluripotent mesenchymal cells. Treatment of mouse pluripotent mesenchymal C3H10T1/2 cells with decalpenic acid gave rise to a morphological change similar to that induced by the treatment with retinoic acid, i.e. the cells adopted a more elongated spindle shape. Using a retinoic acid response element reporter and receptor activity assays, we show that decalpenic acid is a new retinoid with selectivity towards retinoic acid receptors γ and α. The induction of early osteoblastic markers by decalpenic acid was significantly inhibited by treatment with the retinoid antagonist, LE540, or with small interfering RNA-mediated knockdown of retinoic acid receptor γ. These results demonstrated that decalpenic acid induces early osteoblastic markers in pluripotent mesenchymal cells through activation of retinoic acid receptor γ.
Asunto(s)
Ácidos Carboxílicos/farmacología , Diferenciación Celular/efectos de los fármacos , Células Madre Mesenquimatosas/efectos de los fármacos , Naftalenos/farmacología , Osteoblastos/citología , Células Madre Pluripotentes/efectos de los fármacos , Receptores de Ácido Retinoico/agonistas , Animales , Biomarcadores/metabolismo , Diferenciación Celular/genética , Línea Celular , Dibenzazepinas/farmacología , Perfilación de la Expresión Génica , Silenciador del Gen , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Ratones , Osteoblastos/metabolismo , Células Madre Pluripotentes/citología , Células Madre Pluripotentes/metabolismo , Receptores de Ácido Retinoico/genética , Receptor de Ácido Retinoico gammaRESUMEN
Osteoblasts are the cells responsible for bone formation during embryonic development and adult life. Small compounds that could induce osteoblast differentiation might be promising sources of therapies for bone diseases such as osteoporosis. During screening for inducers of osteoblast differentiation of mouse pluripotent mesenchymal C3H10T1/2 cells, we isolated a small compound from the fermentation broth of Penicillium verruculosum CR37010. This compound, named decalpenic acid, bears a decalin moiety with a tetraenoic acid side chain. Treatment of C3H10T1/2 cells with decalpenic acid alone induced the expression of early osteoblast markers, such as alkaline phosphatase activity and osteopontin mRNA, but did not induce the late osteoblast marker osteocalcin mRNA or adipocyte markers under our experimental conditions.
Asunto(s)
Ácidos Carboxílicos/aislamiento & purificación , Macrólidos/aislamiento & purificación , Células Madre Mesenquimatosas/efectos de los fármacos , Naftalenos/aislamiento & purificación , Osteoblastos/efectos de los fármacos , Penicillium/química , Células Madre Pluripotentes/efectos de los fármacos , Fosfatasa Alcalina/genética , Fosfatasa Alcalina/metabolismo , Animales , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacología , Diferenciación Celular/efectos de los fármacos , Línea Celular , ADN/química , ADN/genética , Macrólidos/química , Macrólidos/farmacología , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Ratones , Estructura Molecular , Naftalenos/química , Naftalenos/farmacología , Resonancia Magnética Nuclear Biomolecular , Osteoblastos/citología , Osteoblastos/metabolismo , Células Madre Pluripotentes/citología , Células Madre Pluripotentes/metabolismo , Reacción en Cadena de la Polimerasa , Espectrometría de Masa por Ionización de Electrospray , Espectrofotometría UltravioletaAsunto(s)
Antipaína/química , Antipaína/farmacología , Ganglios Espinales/efectos de los fármacos , Neuronas/efectos de los fármacos , Neurotransmisores/antagonistas & inhibidores , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Sustancia P/antagonistas & inhibidores , Animales , Calcio/metabolismo , Espectrometría de Masas , Estructura Molecular , Ratas , Transmisión Sináptica/efectos de los fármacos , Tripsina/metabolismo , Triptasas/antagonistas & inhibidoresRESUMEN
3-Deoxy-D-manno-octulosonate cytidyltransferase (CMP-KDO synthetase) is involved in the biosynthesis of lipopolysaccharide (LPS) which is an essential component of the outer membrane of gram-negative bacteria. New CMP-KDO synthetase inhibitors, 8-substituted derivatives of 2-deoxy-beta-KDO (2) have been prepared. Compounds 8, 11, 15 and 16 in which the 8-hydroxyl group of 2 is replaced by guanidine, di(carbamoylethyl)amino, p-methoxy- or p-nitro-benzyloxycarbonylamino, respectively affect moderately the CMP-KDO synthetase activity.
Asunto(s)
Disacáridos/síntesis química , Disacáridos/farmacología , Nucleotidiltransferasas/antagonistas & inhibidores , Disacáridos/química , Escherichia coli/enzimología , Modelos Químicos , Estructura MolecularRESUMEN
Sulphostin, a novel dipeptidyl peptidase IV (DPP-IV) inhibitor, was isolated from the culture broth of Streptomyces sp. MK251-43F3. Determination of the absolute configurations of two asymmetric atoms using the natural product was not achieved due to the small amount of the compound obtained. We synthesized four possible stereoisomers of sulphostin from D- or L-ornithine and compared their physicochemical and biological data to naturally isolated sulphostin. As a result, the absolute configurations at C-3 and the phosphorus atom of sulphostin were determined to be S and R, respectively, by X-ray crystallography. Synthetic sulphostin and its C-3 epimer have strong inhibitory activities against DPP-IV, IC50 values of which are 6.0 and 8.9 ng/mL, respectively. Thus it appears that the configuration of the phosphorus atom is primarily responsible for the activity; in contrast, the configuration of C-3 does not appear to affect the activity.