Assuntos
Antioxidantes/isolamento & purificação , Antioxidantes/farmacologia , Sequestradores de Radicais Livres/isolamento & purificação , Sequestradores de Radicais Livres/farmacologia , Fungos Mitospóricos/química , Antioxidantes/química , Sequestradores de Radicais Livres/química , Espectroscopia de Ressonância Magnética , Estrutura MolecularRESUMO
Three novel histamine H3 receptor (H3R) ligands, PF1270A (1), PF1270B (2) and PF1270C (3) were isolated from the culture broth of the fungal strain PF1270. The strain was identified as Penicillium waksmanii on the basis of morphological characteristics. These compounds were obtained from the culture broth by solvent extraction and chromatographic purification. Their structures were established by spectroscopic methods and X-ray crystallographic analysis. They possess pentacyclic spiroindolinone skeletons. 1, 2 and 3 displayed high affinity for the rat H3R (Ki=0.058, 0.17 and 0.19 microM, respectively) and human H3R (Ki=0.047, 0.12 and 0.22 microM, respectively). Moreover, 1, 2 and 3 acted as potent agonists with the EC50 values of 0.12, 0.15 and 0.20 microM, respectively.
Assuntos
Hidrocarbonetos Aromáticos com Pontes/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Penicillium/química , Receptores Histamínicos H3/efeitos dos fármacos , Animais , Hidrocarbonetos Aromáticos com Pontes/isolamento & purificação , Células CHO , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Fenômenos Químicos , Físico-Química , Classificação , Cricetinae , Cricetulus , Cristalografia por Raios X , Fermentação , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Compostos Heterocíclicos com 3 Anéis/isolamento & purificação , Humanos , Técnicas In Vitro , Ligantes , Espectrometria de Massas , Microscopia Eletrônica de Varredura , Modelos Moleculares , Conformação Molecular , Penicillium/classificação , Penicillium/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Histamínicos H3/genética , Espectrometria de Massas de Bombardeamento Rápido de ÁtomosRESUMO
Six novel chymase inhibitors, SF2809-I, SF2809-II, SF2809-III, SF2809-IV, SF2809-V and SF2809-VI, were isolated from the fermentation broth of an actinomycete strain SF2809. The strain was identified as Dactylosporangium sp. by morphological, chemotaxonomical and phylogenetic studies. These six novel compounds inhibited recombinant human chymase in the range between IC50 of 0.014 and 7.3 microM. However, they showed little or no inhibitory activity against chymotrypsin or cathepsin G, even though these two and chymase belong to the chymotryptic serine protease family. This result indicates that these compounds work as specific chymase inhibitors.
Assuntos
Actinobacteria/química , Indóis/farmacologia , Quinolonas/farmacologia , Serina Endopeptidases/metabolismo , Inibidores de Serina Proteinase/farmacologia , Actinobacteria/classificação , Actinobacteria/metabolismo , Metabolismo dos Carboidratos , Quimases , Fermentação , Humanos , Indóis/isolamento & purificação , Microscopia Eletrônica de Varredura , Filogenia , Quinolonas/isolamento & purificação , Proteínas Recombinantes/antagonistas & inibidoresRESUMO
Novel chymase inhibitors, SF2809-I, II, III, IV, V and VI, were isolated from the fermentation broth of Dactylosporangium sp. SF2809, and their structures were determined by spectroscopic analyses. SF2809 compounds commonly contain a substituted indole moiety and a quinolinone moiety. The two moieties are connected to a methylene carbon in SF2809-I and III. The other compounds, SF2809-II, IV, V and VI, have an additional moiety, a p-hydroxyphenyl group or a phenyl group. In these compounds, all of three moieties are connected to a methine carbon. Furthermore, studies concerning the stereochemistry of SF2809-V revealed that the isolated compound was racemic, and the isomer possessing (R)-configuration was about thirty times more potent than another isomer.