RESUMO
In the course of our screening program for vasoactive compounds using co-culture assay of endothelial cells and fibroblast cells, potent activity was detected in the cultured broth of Incrucipulum sp. SANK 10414. Two active compounds, F-36316 A and B, and a non-active homolog, F-36316 C, were isolated from the broth. The structures of F-36316 A, B and C were elucidated by physicochemical data and spectral analyses, and found to be new 3-acylated tetronic acid homologs. F-36316 A and B induced morphological changes of endothelial cells different from vascular endothelial growth factor (VEGF) or vestaines in the assay with EC50 values of 1.8 and 11.7 µM, respectively. Furthermore, F-36316 A and B suppressed VEGF-induced vascular permeability induction in mice.
Assuntos
Ascomicetos/crescimento & desenvolvimento , Ascomicetos/metabolismo , Produtos Biológicos/isolamento & purificação , Permeabilidade Capilar/efeitos dos fármacos , Meios de Cultura/química , Células Endoteliais/efeitos dos fármacos , Animais , Produtos Biológicos/química , Técnicas de Cocultura , Fibroblastos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Análise EspectralRESUMO
We conducted a screening program for vasoactive compounds and detected a potent activity in the cultured broth of Streptomyces sp. SANK 63697. From the cultured broth, two active compounds, vestaine A1 and B1, were isolated. The structures of these compounds were elucidated by physicochemical data and spectral analyses, and found to be new compounds.
Assuntos
Acetilcisteína/análogos & derivados , Compostos de Amônio Quaternário/metabolismo , Streptomyces/metabolismo , Acetilcisteína/química , Acetilcisteína/metabolismo , Acetilcisteína/farmacologia , Fármacos Cardiovasculares/química , Fármacos Cardiovasculares/metabolismo , Fármacos Cardiovasculares/farmacologia , Técnicas de Cocultura , Células Endoteliais/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Humanos , Estrutura Molecular , Compostos de Amônio Quaternário/química , Compostos de Amônio Quaternário/farmacologiaRESUMO
BACKGROUND/AIMS: Vascular endothelial growth factor (VEGF) is a key molecule in the regulation of both angiogenesis and vascular permeability. However, it is known that overproduction of VEGF induces abnormal blood vessel formation and these vessels cause several disease pathologies, such as diabetic retinopathy. The purpose of this study was to find novel vasoactive compounds which have different properties from VEGF. METHODS/RESULTS: We screened a natural product library using a co-culture angiogenic assay of endothelial cells and fibroblasts. By focusing on morphological changes of endothelial cells, we isolated the novel compounds vestaine A1 and vestaine B1 from the cultured broth of an actinomycete strain, Streptomyces sp. SANK 63697. Vestaine A1 enhanced tube formation of endothelial cells in Matrigel and suppressed cell death induced by serum deprivation. Vestaine A1 activated both MEK1/2 and PI-3 kinase pathways independently of the VEGF pathway in a dose- and time-dependent fashion. Finally, vestaine A1 potently suppressed VEGF-induced vascular permeability both in vitro and in vivo. CONCLUSION: Vestaine A1 has the potential to exhibit both pro-angiogenic and anti-permeability properties, and would therefore be useful for therapeutic treatment for abnormal vascular permeability-related diseases.
