A family of novel compounds has been detected and isolated following an assay for the attenuation of multiple drug resistance in tumor cells from the fermentation broth and mycelia of a strain of Aspergillus fischeri which we have designated var. brasiliensis. The structures of three components were determined employing 1-D and 2-D homonuclear and heteronuclear NMRspectroscopy and mass spectrometry. The structure of 5-7V-acetylardeemin was confirmed by single crystal X-ray diffraction.These compounds are most closely structurally related to asperlicin E1}.In the course of screening for compounds which reverse multi-drug resistance to antitumor antibiotics, the ardeemins were isolated from a newstrain of Aspergillus fischeri (designated var. brasiliensis).A companion paper2) describes the taxonomy and fermentation of the producing organism and the biological activities of ardeemin (1) and 5-7V-acetylardeemin (2). This paper will describe the isolation and structures of these novel heterocyclic compounds.Isolation of the Ardeemins Upon completion of the fermentation, 8 liters of acetone was added to 20 liters of whole broth and the mixture was stirred for 3 hours (See Fig. 1). To this was added 16 liters of ethyl acetate and the resultant mixture was stirred for 1 hour at which time the organic layer was removed. Anadditional 16 liters of ethyl acetate was added to the aqueous acetone and the mixture was stirred for 1 hour. The second ethyl acetate layer was removed and added to the first, and the combined ethyl acetate extracts wereconcentrated to an aqueoussuspension which was partitioned between equal volumes of waterchloroform -methanol (1.5 liters of each). The upper layer from this partition was extracted twice with further volumes of chloroform (0.7 liters each time) and these chloroform extracts were combined with the original lower layer and concentrated to an oil. This oil was chromatographed over a Sephadex LH-20 column (8cmx 80cm) eluted with methanol. Active fractions from this column were combined and concentrated to an oil. This oil was
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...
Two novel antifungal antibiotics, named dorrigocin A and B have been isolated fermentation broth and myceliumof Streptomyces platensis subsp. rosaceus. These close compoundswere separated from one another by countercurrent chromatographyon ai planet centrifuge. The structures of the dorrigocins were determined by NMRand IR spe and mass spectrometry. Each is a putative propionate -acetate derived straight chain terminating in cycloheximide. The dorrigocins differ from one another only in their oxidatioIn the course of screening for antifungal antibiotics, two novel glutarimide compoundsdesignated dorrigocin A (1) and B (2) were isolated from Streptomyces platensis subsp. rosaceus. These antibiotics are most closely related to the recently described glutarimide antibiotic BU-4146T(3)1}. This paper will describe the isolation and separation of the dorrigocins and the elucidation of their structures. Two companion papers2'3) describe the isolation, identification and fermentation of the producing culture and a biological evaluation of the dorrigocins. Isolation of the Dorrigocins Upon completion of fermentation, 30 liters of whole broth was treated with XAD-16(3 liters) which was washed with water and eluted with methanol (12liters). The methanol eluate was concentrated to dryness and triturated sequentially with 1 liter portions of; ethyl acetate, methanol, and water. The methanol soluble material was partitioned between hexane, ethyl acetate, methanol and water (0.2 liters of each).The lower layer from this partition was concentrated to dryness and chromatographed over a Sephadex LH-20 column developed with methanol. Active fractions from this column were combined and concentrated to a pale oil. This oil was subjected to countercurrent chromatography on an Ito multilayered coil planet centrifuge in a solvent system of chloroform-methanol-water (1 : 1 : 1) with the lower layer stationary.Active fractions from this columnwere combinedand concentrated to an oil. This oil was subjected to countercurrent chromatography on an Ito multi-layered coil planet centrifuge
A novel complex of antifungal and immunosuppressant compounds has been isolated from the fermentation broth and mycelia of two strains of Streptomyces diastatochromogenes. The structures of eight related components were determined employing ID and 2D homonuclear and heteronuclear NMR spectroscopy and mass spectrometry. These structures represent the first reported spiroketal 24-memberedmacrolide natural products related to the common26-memberedoligomycins.In the course of screening for antifungal antibiotics, two strains of Streptomyces diastatochromogenes were isolated which produced a complex of novel spiroketal 24-memberedmacrolides. Twocompanion papers1'2* describe the taxonomy and fermentation of the producing organisms and the biological activities of the dunaimycins. IsolationAs described in Part I of this series, two strains of S. diastatochromogenes were discovered which produced different members of the dunaimycin complex. Strain AB 1691Q-321 produced dunaimycins Cl, C2, D2, D2S, D3 and D4S. Strain AB171 1J-452 under different conditions produced either dunaimycins Al and D2S or dunaimycins D2S and D3S. The dunaimycins are lipophilic antibiotics and tend to be mainly associated with the mycelia of the producing culture, although some activity can be detected in the filtered broth. Twodifferent approaches have been taken to recovery of the antibiotics from the fermentation mix. Either whole broth was steeped with a solid phase polystyrene resin such as Amberlite XAD-2,a mixture of mycelia and resin was then filtered from the broth and this mixture was washed with water and then extracted with methanol to yield the crude antibiotic complex. Alternatively, the mycelia was removed from the fermentation broth by centrifugation and decanting. The mycelial residue was then extracted with acetone to give the crude antibiotic complex. In this latter method, any antibiotic in the beer and not associated with the mycelia was discarded. This represented only a small fraction of the total antifungal activity. Initial purification was achieved by partitioning of the crude complex in a multicomponent two phase solvent system. Final purification and separation of componentsof the complexwas achieved using a variety of chromatographic methods including Sephadex LH-20 gel exclusion columns, normal phase silica gel columns and high speed countercurrent chromatography on an Ito multi-layered coil planet centrifuge. This yielded eight biogenetically related congeners as chromatographically and spectrally pure compounds with somewhat broad melting ranges. To date none has been obtained crystalline. The detailed purification schemes are outlined in Figs. 1, 2, and 3.
The altromycins are a novel complex of anthraquinone-derived Gram-positive antibiotics with potent antitumor activity. These compounds are produced by an actinomycete, AB 1246E-26 (NRRL 18371), obtained from a South African bushveld soil.1* Altromycins A, B, C, and D, compoundsstructurally related to the pluramycingroup of antibiotics, have been previously reported as has some biological evaluations of the more abundant members.2'3) Sun et ai, has demonstrated that altromycin B forms an intercalated threaded drug-DNA complex that is covalently bound through N7 ofguanine in the major groove and has proposed a prototypic DNAadduct structure for the altromycin-pluramycin antitumor antibiotics.4* AltromycinA R1=NHCH3 R2=OH R3=OH AltromycinB R^NCCH^R2=OH R3=OH AltromycinC R^NHCHa R2=H R3=OH AltromycinD R!=N(CH3)2 R2-H R3=OH R! =NHCH3
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