Assuntos
Acremonium/metabolismo , Interleucina-4/antagonistas & inibidores , Pirrolidinonas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Acremonium/crescimento & desenvolvimento , Linhagem Celular , Células HeLa , Humanos , Concentração Inibidora 50 , Interleucina-4/metabolismo , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Pirrolidinonas/química , Pirrolidinonas/isolamento & purificação , Pirrolidinonas/farmacologiaRESUMO
A novel inhibitor of STAT6 activation, named as TMC-264 (1), was discovered from the fermentation broth of Phoma sp. TC 1674. Based on spectroscopic analyses, TMC-264 was found to be a novel tricyclic polyketide with chloro-1H-dibenzo[b,d]pyran-4,6-dione. TMC-264 suppressed expression of IL-4 driven luciferase and germline Cepsilon mRNA with IC50 values of 0.3 microM and 0.4 microM, respectively. TMC-264 exhibited a potent inhibitory activity against tyrosine phosphorylation of STAT6 with an IC50 value of 1.6 microM, whereas TMC-264 weakly inhibited tyrosine phosphorylation of STAT5 with an IC50 value of 16 microM, but did not inhibit the phosphorylation of STAT1 up to 40 microM. TMC-264 blocked formation of the complexes between phosphorylated STAT6 and STAT6 oligonucleotides in a dose dependent manner, while TMC-264 did not affect the formation of phosphorylated STAT1/STAT1 oligonucleotides complexes. These results suggested that TMC-264 selectively inhibited IL-4 signaling by interfering both of phosphorylation of STAT6 and binding of the phosphorylated STAT6 to the recognition sequence.
Assuntos
Compostos Heterocíclicos com 3 Anéis/farmacologia , Transativadores/antagonistas & inibidores , Cromatografia Líquida de Alta Pressão , Interações Medicamentosas , Fermentação , Células HeLa , Compostos Heterocíclicos com 3 Anéis/isolamento & purificação , Humanos , Interleucina-4/farmacologia , Fosforilação/efeitos dos fármacos , Fator de Transcrição STAT6 , Transdução de Sinais/efeitos dos fármacosRESUMO
[structure: see text] TMC-264 (1), a novel tricyclic heptaketide with a unique chloro-1H-dibenzo[b,d]pyran-4,6-dione skeleton, was discovered from the fungus Phoma sp. TC 1674. The structure was elucidated on the basis of NMR analyses of normal abundance and biosynthetically (13)C-enriched TMC-264. TMC-264 showed potent inhibitory activity against tyrosine phosphorylation of STAT6.
Assuntos
Fungos/química , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/isolamento & purificação , Fungos/classificação , Compostos Heterocíclicos com 3 Anéis/farmacologia , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Fosforilação/efeitos dos fármacos , Fosfotirosina/metabolismo , Fator de Transcrição STAT6 , Transativadores/metabolismoRESUMO
New inhibitors of IL-4 signal transduction, designated as TMC-256A1 and C1, were discovered together with TMC-256B1, a previously known dihydronaphthopyrone, from the fermentation broth of Aspergillus niger var niger TC 1629 by using an IL-4 driven reporter gene assay. Based on spectroscopic analyses, TMC-256A1 and C1 were found to be new members of the naphthopyrone antibiotics. TMC-256A1, B1 and C1 inhibited the IL-4 driven luciferase activity with IC50 values of 25 microM, 30 microM and 1.7 microM, respectively in this assay system. Furthermore, these compounds inhibited the expression of germline C epsilon mRNA with IC50 values of 6.6 microM , 34 microM and 0.31 microM, respectively.
