Mevinolin, a fungal metabolite, was isolated from cultures of Aspergillus terreus. The structure and absolute configuration of mevinolm and its open acid form, mevinolinic acid, were determined by a combination of physical techniques.
Much current attention focuses on the renin-angiotensin system in relation to mechanisms controlling blood pressure and renal function. Recent demonstrations (ref. 1, ref. 2 and refs therein) that angiotensin-converting enzyme inhibitors show promising clinical antihypertensive properties have been of particular interest. We now report on the design of a novel series of substituted N-carboxymethyl-dipeptides which are active in inhibiting angiotensin-converting enzyme at nanomolar levels. We suggest that these compounds are transition-state inhibitors and that extensions of this design to other metalloendopeptidases merit further study.
The avermectins, a family of new anthelmintic agents, were isolated from the mycelia of Streptomyces avermitilis. Four closely related major components and four homologous minor components were separated from the complex. Solvent extraction, solvent partition, and adsorption methods were used to isolate and purify the complex; novel partition chromatography systems using Sephadex LH-20 were used to separate the components. A reverse-phase high-pressure liquid chromatography assay for the quantitative determination of all components was used extensively to monitor the purification methods.The avernectin complex, a family of new anthelmintic agents, is produced by fermentation of Streptomyces avermitilis (NRRL 8165), as described in a separate publication (1).The complex contains four closely related major components, Ala, A2a, Bia, and B2a, in varying proportions and four minor components, Alb, A2b, Blb, and B2b, each of which is a lower homolog ofthe corresponding major component. The structures and physicochemical properties of all components are the subject of a separate publication (G. Soc., in press).In this report, the isolation of the complex from broth, the separation of all of its components, and the chromatographic properties of each will be described. For the sake of simplicity, mixtures of homologs will be designated by omis- B2a, 6.74; A2b, 7.22; A2s, 8.00; B,I, 8.32; B,I., 9.70; Al,b, 11.06; and A,,, 11.78. The UV monitor was set at 246 nm to improve the resolution of a major impurity which exhibited a UV maximum at a lower wavelength. Although the UV maximum for avermectins occurred at 245 nm, sensitivity was only slightly reduced at 246 nm, whereas the sensitivity for the impurity was reduced substantially. The UV spectrum of B21 is given in Fig. 1 and is characteristic of all components. Recordings of high-pressure liquid chromatography (HPLC) assays of standard and unknown solutions are given in Fig. 2. RESULTSIsolation of avermectin complex. Approximately 8,000 liters of fermentation broth was filtered, and the cake was washed with water. The wet cake was then slurried in 3,000 liters of acetone, filtered, and washed with 400 liters of 80% acetone. The cake was discarded, and the combined extract and wash were concentrated to 800 liters. The concentrate was adjusted to pH 5 with dilute HCl and then extracted twice with 800-liter portions of methylene chloride.
HPLCbioautography of the directed biosynthesis of Zalerion arboricola led to the discovery of pneumocandin Bo (L-688,786), a new antifungal and anti-Pneumocystis carinii lipopeptide. Isolation techniques were developed to separate this componentfrom pneumocandinAo(L-67 1 ,329) in fermentations of a mutant of Zalerion arboricola. Anumberof related compounds were also isolated, which differ from pneumocandinsAoand Bo in the hydroxylation patterns on the ornithine, homotyrosine, and proline. Aculeacin1 '2) and echinocandin B3'4) are representatives of a large class of naturally-occuring antifungal lipopeptides which are characterized by potent fungicidal activity against Candida sp. A semi-synthetic derivative ofechinocandin B, cilofungin, has been shown to protect animals with systemic fungal infections. 5) Another representative, pneumocandin Ao (L-671,329),6~8) is active against Pneumocystis carinii6~9) an important opportunistic organism which causes pneumonia in AIDS patients. The commonmechanism of action against these two pathogens is presumed to be inhibition of l,3-/?-glucan synthesis.9) This paper describes the discovery, production, and isolation of pneumocandin Bo and related lipopeptides, which have biological activity against both Candida sp. and P. carinii. Materials and Methods Identification of the Producing Strain The strain of Zalerion arboricola Buczacki (ATCC20868) was recovered from filtrates of water and sediments from a farm pond in the Valle del Rio Lozoya, near Madrid, Spain. This unusual isolate was sent to the Centraalbureau voor Schimmelcultures, Baarn, The Netherlands, where Dr. G. S. DeHoog made the original identification. The characteristics of this strain coincide well with the original descriptions of Buczacki10) and with the comparative treatment of the original strain by Goos.n) In the description of the organism presented in the "Results and Discussion" section, capitalized color namesare from Ridgway.12) Analytical and Preparative HPLCSystems HPLCanalysis of pneumocandin Bo was performed on a system consisting of a Spectra-Physics 8700 pump, a Spectra-Physics 8780 autoinjector, a DuPont Zorbax ODS4.6mm i.d. x 25 cm column, an LKB 2151 variable wavelength UVdetector equipped with a 10 mmpathlength cell and a Spectra-Physics 4200 integrator. Column temperature was maintained constant at 40°C via jacketing and a constant temperature bath. The isocratic solvent system was CH3CN-H2O(45 : 55), the flow rate was 1.0ml/minute, and the UVabsorbance of the effluent was monitored at 210nm. Under these conditions the retention times of
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