RESUMO
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.
Assuntos
Actinomycetales/química , Dinoprostona/antagonistas & inibidores , Naftoquinonas/isolamento & purificação , Naftoquinonas/farmacologia , Antagonistas de Prostaglandina/isolamento & purificação , Antagonistas de Prostaglandina/farmacologia , Dinoprostona/metabolismo , Relação Dose-Resposta a Droga , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Naftoquinonas/química , Ressonância Magnética Nuclear Biomolecular , Antagonistas de Prostaglandina/química , Sarcoma Sinovial/tratamento farmacológicoRESUMO
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.
Assuntos
Ácidos Carboxílicos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Células-Tronco Mesenquimais/efeitos dos fármacos , Naftalenos/farmacologia , Osteoblastos/citologia , Células-Tronco Pluripotentes/efeitos dos fármacos , Receptores do Ácido Retinoico/agonistas , Animais , Biomarcadores/metabolismo , Diferenciação Celular/genética , Linhagem Celular , Dibenzazepinas/farmacologia , Perfilação da Expressão Gênica , Inativação Gênica , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Osteoblastos/metabolismo , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/metabolismo , Receptores do Ácido Retinoico/genética , Receptor gama de Ácido RetinoicoRESUMO
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.
Assuntos
Ácidos Carboxílicos/isolamento & purificação , Macrolídeos/isolamento & purificação , Células-Tronco Mesenquimais/efeitos dos fármacos , Naftalenos/isolamento & purificação , Osteoblastos/efeitos dos fármacos , Penicillium/química , Células-Tronco Pluripotentes/efeitos dos fármacos , Fosfatase Alcalina/genética , Fosfatase Alcalina/metabolismo , Animais , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , DNA/química , DNA/genética , Macrolídeos/química , Macrolídeos/farmacologia , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Estrutura Molecular , Naftalenos/química , Naftalenos/farmacologia , Ressonância Magnética Nuclear Biomolecular , Osteoblastos/citologia , Osteoblastos/metabolismo , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/metabolismo , Reação em Cadeia da Polimerase , Espectrometria de Massas por Ionização por Electrospray , Espectrofotometria UltravioletaAssuntos
Antipaína/química , Antipaína/farmacologia , Gânglios Espinais/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurotransmissores/antagonistas & inibidores , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Substância P/antagonistas & inibidores , Animais , Cálcio/metabolismo , Espectrometria de Massas , Estrutura Molecular , Ratos , Transmissão Sináptica/efeitos dos fármacos , Tripsina/metabolismo , Triptases/antagonistas & inibidoresRESUMO
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.
Assuntos
Dissacarídeos/síntese química , Dissacarídeos/farmacologia , Nucleotidiltransferases/antagonistas & inibidores , Dissacarídeos/química , Escherichia coli/enzimologia , Modelos Químicos , Estrutura MolecularRESUMO
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.
