RESUMO
Aspergillus fumigatus TP-F0196 produces pseurotin A, synerazol and gliotoxin. Phenylalanine is a common biosynthetic precursor of these antibiotics. Feeding fluorophenylalanine to the culture induced the production of novel fluorinated analogs. These fluorinated antibiotics were obtained from the culture broth by solvent extraction and purified by chromatographies, and their antimicrobial and antitumor activities were investigated. Among the novel fluorinated analogs, 19- and 20-fluorosynerazols exhibited potent anti-angiogenic activity in the chorioallantoic membrane assay. In addition, 19-fluorosynerazol showed more potent cytocidal activity against several cancer cell lines than synerazol.
Assuntos
Antifúngicos/biossíntese , Aspergillus fumigatus/metabolismo , Fluoretos/metabolismo , Gliotoxina/biossíntese , Imunossupressores/metabolismo , Inibidores da Angiogênese/farmacologia , Antifúngicos/farmacologia , Bactérias/efeitos dos fármacos , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Ensaios de Seleção de Medicamentos Antitumorais , Fermentação , Fluoretos/química , Gliotoxina/farmacologia , Humanos , Imunossupressores/farmacologia , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Testes de Sensibilidade Microbiana , Pirrolidinonas/farmacologiaRESUMO
In the screening of novel antifungal compounds, yatakemycin was found in the culture broth of Streptomyces sp. TP-A0356. Yatakemycin was obtained by solvent extraction of the fermentation broth and chromatographic purification using ODS column and preparative HPLC. The structure of yatakemycin was elucidated by NMR and CID-MS/MS experiments as a novel antibiotic belonging to a family of CC-1065 and duocarmycins known to be DNA alkylating agents. Yatakemycin inhibited the growth of pathogenic fungi such as Aspergillus fumigatus and Candida albicans with the MIC values of 0.01-0.03 microg/ml, more potent than amphotericin B (MIC: 0.1-0.5 microg/ml) or itraconazole (MIC: 0.03-0.2 microg/ml). It also showed potent cytotoxicity against cancer cell lines with the IC50 of 0.01-0.3 microg/ml.
Assuntos
Antifúngicos/química , Indóis/química , Pirróis/química , Pirrolidinonas/química , Streptomyces/química , Antifúngicos/biossíntese , Antifúngicos/isolamento & purificação , Antifúngicos/farmacologia , Aspergillus fumigatus/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Cromatografia em Gel , Cromatografia Líquida de Alta Pressão , Duocarmicinas , Fermentação , Indóis/isolamento & purificação , Indóis/farmacologia , Testes de Sensibilidade Microbiana , Microscopia Eletrônica de Varredura , Estrutura Molecular , Peso Molecular , Ressonância Magnética Nuclear Biomolecular , Pirróis/isolamento & purificação , Pirróis/farmacologia , Pirrolidinonas/isolamento & purificação , Pirrolidinonas/farmacologia , Espectrometria de Massas de Bombardeamento Rápido de Átomos , Espectrofotometria Infravermelho , Espectrofotometria Ultravioleta , Streptomyces/classificação , Streptomyces/metabolismoRESUMO
A novel inhibitor for anchorage-independent growth of tumor cells was isolated from the culture broth of a fungal strain. The producing strain TP-F0213 was identified as Penicillium aurantiogriseum Dierckx based on the taxonomic study. The compound designated anicequol was obtained by solvent extraction, HP-20 and silica gel chromatographies and recrystallization. The planar structure was elucidated by NMR analysis to be 16-acetoxy-3,7,11-trihydroxyergost-22-en-6-one. The absolute configuration was determined by the X-ray analysis of 3,7-bis-p-bromobenzoyl derivative. The carbon skeleton of anicequol has the same absolute configuration as ergostane and the configurations of substituents are 3beta, 5alpha, 7beta, 11beta, 16beta and 24S. Anicequol inhibited the anchorage-independent growth of human colon cancer DLD-1 cells with the IC50 of 1.2 microM whereas the IC50 against anchorage-dependent growth was 40 microM.
