RESUMEN
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.
Asunto(s)
Antifúngicos/biosíntesis , Aspergillus fumigatus/metabolismo , Fluoruros/metabolismo , Gliotoxina/biosíntesis , Inmunosupresores/metabolismo , Inhibidores de la Angiogénesis/farmacología , Antifúngicos/farmacología , Bacterias/efectos de los fármacos , Línea Celular Tumoral , Cromatografía Líquida de Alta Presión , Ensayos de Selección de Medicamentos Antitumorales , Fermentación , Fluoruros/química , Gliotoxina/farmacología , Humanos , Inmunosupresores/farmacología , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Pruebas de Sensibilidad Microbiana , Pirrolidinonas/farmacologíaRESUMEN
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.
Asunto(s)
Antifúngicos/química , Indoles/química , Pirroles/química , Pirrolidinonas/química , Streptomyces/química , Antifúngicos/biosíntesis , Antifúngicos/aislamiento & purificación , Antifúngicos/farmacología , Aspergillus fumigatus/efectos de los fármacos , Candida albicans/efectos de los fármacos , Cromatografía en Gel , Cromatografía Líquida de Alta Presión , Duocarmicinas , Fermentación , Indoles/aislamiento & purificación , Indoles/farmacología , Pruebas de Sensibilidad Microbiana , Microscopía Electrónica de Rastreo , Estructura Molecular , Peso Molecular , Resonancia Magnética Nuclear Biomolecular , Pirroles/aislamiento & purificación , Pirroles/farmacología , Pirrolidinonas/aislamiento & purificación , Pirrolidinonas/farmacología , Espectrometría de Masa Bombardeada por Átomos Veloces , Espectrofotometría Infrarroja , Espectrofotometría Ultravioleta , Streptomyces/clasificación , Streptomyces/metabolismoRESUMEN
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.
