Four novel platelet activating factor (PAF) antagonists, Sch 47918, Sch 49026, Sch 49027 and Sch 49028, were isolated from the fermentation broth of the fungal culture, Phomasp. (ATCC 74077). The structures of these compoundswere elucidated by spectroscopic methods. The structure and stereochemistry of the first isolated component, Sch 47918, were confirmed by single crystal X-ray diffraction analysis. Sch 49028, the most active component, was found to inhibit PAF-induced human platelet aggregation in vitro with an IC50 of 1.26 /zm. However, this compound was inactive in vivo at 5 mg/kg, iv against PAF-induced bronchospasm in guinea pigs.is a potential mediator of allergic1 '2) and non-allergic inflammatory3) diseases. PAF binds to specific receptors on various cell types leading to diverse biological responses including platelet aggregation, leukocyte activation and hypotension.40 The PAF receptor is a very attractive target for developing a new type of anti-allergic and anti-inflammatory drug. In recent years, the search for PAF antagonists has led to the discovery of a number of new natural products from microbial origin.5~8) However, a majority of these compounds possesses the dialkylthiopiperazinedione moiety.9) In the course of our screening program for novel PAF inhibitors, four macrocyclic compounds were discovered from the fermentation broth of a fungal culture. These compoundsrepresent an uncommon 14-memberedmacrocyclic ring system with a bridged 6-memberedring. In this report, we describe the details of the identification and fermentation of the producting culture, the isolation, physico-chemical properties, structure elucidation and biological activities of the pure compounds. Experiment al TaxonomyAgar plugs, 2 x 2mm, from 10 to 14-day old malt extract agar slants, incubated at 22°C, were used as the inoculum for morphological and cultural characteristics. Morphological characteristics were observed on plates of malt extract agar10) incubated at 22°C for 10 to 12 days. Culture characteristics were observed on petri dishes containing malt extract, malt yeast, potato dextrose and Czapek's Dox agars10) after 12 days at 22°C in the dark. FermentationThe initial stage inoculum for the fermentation of the PAFantagonists was prepared by transferring 2.5ml of a frozen whole broth (at -20°C) to 50ml of germination medium in 250ml Erlenmeyer flasks. The germination medium (g/liter) consisted of Proteose peptone #3, 0.5%; sodium chloride, 0.5%; glucose, 2%; yeast extract, 0.3%; soy grits, 0.5%; and sodium potassium phosphate (monobasic) 0.5%. The pH
Three novel antifungal antibiotics, Sch 38518, Sch 39185 and Sch 38516 were isolated from the fermentation broths of two actinomycetes identified by chemical, morphological and physiological analysis as a new species of Actinomadura. The compoundswere isolated from broth by solvent extraction and purified by silica gel chromatography. Physico-chemical properties, mass spectral analysis, IR and UVsuggested the compounds were similar. Sch 38518 and Sch 39185 have a molecular formula of C25H48N2O5. *H NMR, 13C NMRand hydrolysis indicated the aglycones were identical, however the compounds differed in containing isomeric sugar moieties. Sch 38518 contains mycosamine while Sch 39185 contains 3,6-dideoxy-3-amino-L-talopyranose.Sch 38516 has a molecular formula of C24H46N2O5and is a lower homolog of Sch 39185. The three compounds, Sch 38518 (1), Sch 39185 (2), and Sch 38516 (3) exhibit similar activity against Candida spp. with geometric mean MICs of 1.81, 2.00 and 0.91 /xg/ml, respectively.A directed search for rare actinomycetes capable of producing novel secondary metabolites resulted in the isolation of a group offilamentous organisms producing antifungal antibiotics active in a mechanistic assay that detects inhibitors of fungal cell envelope integrity.1} Twoof the producing strains, SCC 1776 and SCC1 777, were identified as members of the genus Actinomadura. The isolated and purified compounds were found to be membersof a newclass of antifungal antibiotics characterized by the presence of a 14 membered macrocyclic lactam.2~8)In this report, the taxonomy and fermentation of both cultures, and the isolation, physico-chemical properties, and biological activities of these compoundsare described. TaxonomyThe producing strains, SCC1776 and SCC 1777, were isolated from deciduous forest soil samples. Soils were suspended in distilled water and aliquots steaked onto the surface of plating mediumcontaining glycerol, 0.1%; yeast extract, 0.1%; agar, 1.5%; and rosaramicin9) 10/zg/ml. Discreet colonies developed after 14-21 days at 28~30°C.The isolates are Gram-positive, filamentous organisms forming yellow-brown vegetative mycelial pigments and aerial mycelia approximately 0.5 to 1.0fim in diameter that fragment into chains of 5 to 29 spores. Spore chains are straight, hooked, irregularly curved or arranged in spirals of 2 to 5 turns. The spores are round to ovoid, 0.8 to 1.1 /mi in diameter. By electron microscopy the spore surface appears
A novel polycyclic xanthone, Sch 42137, related to the albofungin family of compounds was isolated from culture broth. Its structure was determined by detailed spectroscopic studies and comparison of circular dichroic studies to related compoundsalbofungin and simaomicin. Sch 421 37 exhibited MICvalues < 0. 1 25^g/ml against yeasts and dermatophytes. Details are presented herein.
3H and 14C‐Sch 27899 have been prepared by fermentation using the Micromonospora carbonacea organism. In the case of 3H‐Sch 27899, the label was incorporated by a single addition of 100 mCi of 70Ci/mmole L‐[3H‐methyl]‐methionine to two flasks. For 14C‐Sch 27899, 48 mCi of 55 mCi/mmole L‐[14C‐methyl]‐methionine was added in five aliquots to five flasks over a five day period. Both batches were isolated by solvent extraction, oxidized and purified by column chromatography and hplc. An overall incorporation of 7.8% was found from L‐[3H‐methyl]‐methionine and 18.7% from L‐[14C‐methyl]‐methionine. The in vivo stability of label of 3H and 14C‐Sch 27899 was determined, with 14C‐Sch 27899 found to be a better choice for use in in vivo metabolism studies. Copyright © 1999 John Wiley & Sons, Ltd.
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