The ardeemins are a new family of secondary metabolites produced by submerged fermentation of a fungus which was isolated from a soil sample collected in Brazil. Based on taxonomic studies, the producing culture was identified as Aspergillus fischeri var. brasiliensis strain AB 1826M-35. 5-7V-Acetylardeemin potentiated the cytotoxicity of the anticancer agent vinblastine in multidrug resistant humantumorcells.Multidrug resistance (MDR)is characterized by the development of resistance to several structurally unrelated anticancer agents and is a major cause of failure of cancer chemotherapy. The appearance of a specific glycoprotein, P-170, is generally associated with resistant cells1*. P-170 is a membrane associated glycoprotein thought to actively export cytotoxic compoundssuch as anthracyclines and Vinca alkaloids from resistant tumor cells2). Although several compoundsare knownto reverse MDR, none are used clinically because of adverse side effects3*. In the course of screening for modulators of MDR, we discovered a family of novel compounds which we have called ardeemins. 5-JV-Acetylardeemin appears to be the most efficacious of these compoundsin the reversal of MDR. The compoundsare produced in the fermentation broth of Aspergillus fischeri var. brasiliensis strain AB 1826M-35. This paper describes the taxonomy and the fermentation of the producing microorganism and the biological activity of ardeemin and 5-7V-acetylardeemin. The isolation and structural elucidation of these and other congeners are described in an accompanying publication4*. Materials and Methods MicroorganismsStrain AB1826M-35 was isolated from soil collected in Brazil. A subculture of the microorganism was deposited at

Three novel compounds, named the aselacins, which inhibit the binding of endothelin to its receptor have been isolated from two related Acremonium species of fungi grown in stationary culture. These compounds are cyclic pentapeptolides with a ring formed by cyclo[Gly-D-Ser-D-Trp-/?-Ala-L-Thr] and an additional exocyclic D-Gln to which is attached a functionalized long chain fatty acid. The aselacins differ in the functionalization of this acid. The structures of the aselacins weredetermined by amino acid analysis, mass spectrometry and evaluation of 1-D and 2-D homonuclear and heteronuclear^H, 13C and 15N NMRspectra in protic and aprotic solvents. The stereochemistry of the amino acids present was elucidated by chiral HPLCof hydrolyzed compound.In the course of screening for compounds which inhibit binding of endothelin to its receptor, three novel cyclic pentapeptolides have been isolated from the fungi AB 2093T-194 and AB 2086L-51 grown in stationary culture. A companion paper1} describes the taxonomy and growth of the producing culture as well as the biological evaluation of the aselacins (1~3). This paper will discuss the isolation of aselacin A, B and C and the elucidation of their structures. Isolation of Aselacins A and B As described in the preceding paper1}, the fungus AB2093T-194 was grown in stationary culture. After 21 days of growth in four, 20 liters carboys (the four containing a total of 5.6 liters of liquid medium on 2.4 kg of shredded wheat), acetone (1.2 liters) was added to the fungal mass and media and the mixture was allowed to sit at room temperature for six hours after which a mixture oftoluene -ethyl acetate (0.75 liters of each) was added and the mixture was left overnight at 4°C. Solvent was then removed from the solid mass and concentrated to a brownoil. This oil was partitioned between heptane -methanol -water -acetic acid (5liters:3liters:2liters:0.02liter) and the lower layer was concentrated to an oil. This oil was triturated sequentially with heptane, ethyl acetate, ethanol and methanol (2 liters of each). The ethanol soluble material was chromatographed on a Sephadex LH-20column developed in methanol. The ability of fractions to displace radioactive endothelin from tissue preparations was assayed as described1}. Active fractions from the LH-20column were combined, concentrated to dryness and subjected to countercurrent chromatographyon an Ito multi-layered coil planet centrifuge in a solvent system ofethyl acetate -ethanolwater (2 : 1 : 2) with the lower phase stationary. Active fractions from this column were combined based upon their behavior on thin layer chromatography (TLC) and dried to yield pure aselacin A (1, 241 mg) and a clear oil of mixed components. This oil was subjected to countercurrent chromatography on an Ito multi-layered coil planet centrifuge in a solvent system of chloroform-methanol -water (1 : 1 : 1) with the lower phase stationary. Active fractions from this column were combined based upon their TLCbehavior to yield pure aselacin A (9mg) and pure aselacin...

The benzanthrins, which were produced by Nocardia lurida, were extracted from the fermentation broth with CH2Cl2. Subsequent purification on Sephadex LH-20 and diolbonded silica gel, followed by countercurrent chromatography, afforded analytically pure benzanthrins A and B. FAB-MS revealed that benzanthrins A and B were isomeric. It was demonstrated through degradative and spectroscopic studies that the benzanthrins were di- Fermentation studies with Nocardia lurida, a known producer of the ristocetins, resulted in the additional production of two new antibiotics, benzanthrins A and B. The discovery, fermentation and antibacterial activity of the benzanthrins is the subject of the preceding paper1). This paper will deal with the isolation, structure determination and antitumor activity of these novel antibiotics. ExperimentalGeneral Procedures NMR spectra were obtained with a General Electric GN 500 MHz spectrometer. The samples were run in CD2Cl2 and referenced on the lock solvent (5.32 ppm). The 2D proton-carbon chemical shift correlation (CSCM) experiment was performed on the GN 500 using a 5 mm C-13 probe and a model 1280 computer. The CSCM pulse sequence employed for the experiment was essentially that of FREEMAN and MORRIS2) modified to deliver a composite 180 degree pulse. Ninety degree pulse widths on the 5 mm C-13 probe were 15 pseconds for carbon and 30 useconds for proton. Fixed delays, delta 1 and delta 2, were set to 3.3 and 1.7 mseconds, respectively, with phase-cycling providing quadrature in both dimensions. The 2D homonuclear J-correlation experiment (COSY)3) was run on the GN 500 spectrometer using the 5 mm H-1 probe. The ninety degree proton pulse for this probe was 12 pseconds. Mass spectra were determined on a Kratos MS-50 spectrometer. High resolution measurements were made at 10,000 resolving power. UV spectra were determined with a Perkin-Elmer Lambda 3B UV/VIS spectrophotometer and IR spectra were measured with a PerkinElmer Model 521 grating spectrometer.

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A whole-cell Candida albicans assay based on the protection of growth with sorbitol and characterization of changes in cell morphology, was used to detect novel antifungal agents, inhibitors of fungal cell wall syn

The fusacandins, antifungal agents of the papulacandin class, are produced by a strain of Fusarium sambucinum. Fermentation yielded 60mg/liter of fusacandin A and minor amounts of fusacandin B. As expected, the fusacandins inhibit (l ,3)-/?-glucan synthesis. Fusacandin A is slightly less active than papulacandin B against Candida albicans and, like papulacandin, loses activity in the presence of serum.

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Aselacins, Novel Compounds that Inhibit Binding of Endothelin to Its Receptor. Part 2. Isolation and Elucidation of Structures.-From two related Acremonium species of fungi grown in stationary culture the cyclic title pentapeptolides (I) are isolated. These aselacins A, B and C differ in the functionalization of the fatty acid part. -(HOCHLOWSKI, J. E.; HILL, P.; WHITTERN, D. N.; SCHERR, M. H.; RASMUSSEN, R. R.; DORWIN, S. A.; MCALPINE, J. B.; J. Antibiot. 47 (1994) 5, 528-535; Pharm. Prod. Res. Dev., Abbott Lab., Abbott Park, IL 60064, USA; EN)