RESUMO
In the course of our screening to identify novel PPAR-gamma modulators for the potential treatment of type 2 diabetes, four new chlorinated angucyclinones, chlorocyclinones A-D ( 1- 4), were isolated from the mycelium of Streptomyces sp. strain DSM 17045. Their structures were established by spectroscopic methods. Chlorocyclinones antagonize rosiglitazone-induced peroxisome proliferator-activated receptor gamma (PPAR-gamma) activation with IC 50's < 0.4 microM in vitro using an AlphaScreen assay and are able to displace rosiglitazone from the PPAR-gamma ligand-binding domain (LBD) in a scintillation proximity assay (SPA). The compounds proved to be active in a cell-based reporter gene assay as well, antagonizing rosiglitazone-induced PPAR-gamma activity with IC 50 values between 0.60 and 7.0 microM. Chlorocyclinone C ( 3) exhibited the most potent activity in all assays.
Assuntos
Antraquinonas/isolamento & purificação , Antraquinonas/farmacologia , Hidrocarbonetos Clorados/isolamento & purificação , Hidrocarbonetos Clorados/farmacologia , PPAR gama/efeitos dos fármacos , Streptomyces/química , Tiazolidinedionas/farmacologia , Antraquinonas/química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Hidrocarbonetos Clorados/química , Concentração Inibidora 50 , Luciferases/genética , Luciferases/metabolismo , Estrutura Molecular , Rosiglitazona , Tiazolidinedionas/farmacocinéticaRESUMO
Three new secondary metabolites, 2,5-dihydroxy-3-(3,4-dihydroxyphenyl)-6-phenyl-1,4-benzoquinone (3), 2,5-dihydroxy-3-phenyl-6-(3,4,5-trihydroxyphenyl)-1,4-benzoquinone (4), and 2,7,8-trihydroxy-3-phenyl-1,4-dibenzofurandione (5), as well as two known natural products were isolated from the fungus Stilbella sp. strain 1586. The structures of these compounds were established by spectroscopic and chemical methods. The terphenylquinones 3-5 exhibited significant activity against human src protein tyrosine kinase.
Assuntos
Benzofuranos/isolamento & purificação , Benzoquinonas/isolamento & purificação , Inibidores Enzimáticos/isolamento & purificação , Fungos/química , Quinases da Família src/antagonistas & inibidores , Benzofuranos/química , Benzofuranos/farmacologia , Benzoquinonas/química , Benzoquinonas/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Quinases da Família src/metabolismoRESUMO
A new bicyclic 19-peptide, BI-32169, has been isolated from the culture broth of Streptomyces sp. (DSM 14996). Its structure has been established by amino acid analysis, mass spectrometry, and 2D NMR analysis. BI-32169 consists exclusively of protein amino acids and is cyclized from the side chain of Asp(9) to the N-terminus of Gly(1). One disulfide bond between Cys(6) and Cys(19) forms a bicyclic structure. BI-32169 and its methyl ester derivative showed potent inhibitory activity against the human glucagon receptor (IC(50) 440 and 320 nM, respectively) in a functional cell-based assay.
