Sch 52900 (1) and Sch 52901 (2), two new inhibitors of c-fos proto-oncogene induction, have been isolated from the fermentation broth of the fungal culture (SCF-1 168), Gliocladium sp. Along with compounds 1 and 2, a known compound verticillin A (3) was also obtained from the culture. Structure elucidation of 1 and 2, accomplished by analysis of spectral data in comparison with the data of 3, revealed both 1 and 2 were found to be closely related to the verticillin family of diketopiperazines. All three compoundsprevented serum-stimulated transcription of the humanc-fos promoter, using afos/lac Z reporter gene assay, with IC50 values of 1.5, 18 and 0.5fM for 1, 2 and 3, respectively. Northern analysis revealed that exposure of cells to compound3 causes inhibition of both phorbol ester-induced c-fos induction and serum-induced JE induction in the absence of inhibiting RNAsynthesis, as measured by [3H]uridine incorporation. These results suggest that this class of compounds exerts antitumor activity by blocking a signal transduction pathway that is commonto and necessary for the induction of at least a subset of immediate early genes involved in cell proliferation.

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A novel antifungal agent, Sch 54445, was isolated from the fermentation broth of an Actinoplanes species. Sch 54445 was identified as a polycyclic xanthone related to the albofungin family of compounds on the basis of analyses of spectroscopic data. As a broad-spectrum antifungal agent, Sch 54445 exhibits highly potent activities against various yeasts and dermatophytes with MIC values approximately 0.00038 microgram/mL.

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