Structure of the Spiroketal-macrolide Ossamycin.

Abstract

Ossamycin is a cytotoxic agent of undetermined structure that was originally isolated in 1965 from culture broths of Streptomyces hygroscopicus var. ossamyceticus. Its overall structure and relative stereochemistry have now been determined by single crystal X-ray diffraction studies. Absolute stereochemistry was established according to the previously determined configuration of its aminosaccharide constituent, ossamine. The aglycone of ossamycin possesses a 24-membered macrolide ring system onto which is incorporated both a 6,6-spiroketal and a 5-membered hemiketal ring system. The overall three-dimensional structure possesses features in commonwith the related macrocyclic antibiotics dunaimycin, cytovaricin, and A82548A.Ossamycin is a fermentation-derived natural product that was originally reported in 1965 as a novel cytotoxic agent isolated from culture broths of Streptomyces hygroscopicus var. ossamyceticus.^However, its structure has remained unknown until now. Preliminary studies in 1969 had shown that ossamycin contained an unusual aminodeoxysaccharide that was given the name, ossamine.2) This amino sugar and its enantiomer have been prepared by several total syntheses and are well characterized.2~5) Aminodeoxy sugars such as ossamine are typically found in macrolides and other polyketide-derived fermentation products.6) Ossamine itself has been recently proposed as a constituent of the novel tetracyclic insecticidal macrolide, spinosyn G (factor G of the A83543 complex).7) As a result of our continuing interest in this large and structurally diverse class of polyketide-derived natural products, we have now determined the structure of ossamycin by single crystal diffraction X-ray crystallography (Fig. 1).Isolation and Characterization The sample ofossamycin was obtained by fermentation of its producing organism, Streptomyces hygroscopicus var. ossamyceticus, that was obtained from the American Type Culture Collection (Rockville, Md.) where it had been originally deposited by the Bristol-Myers Company under accession number 15420. Ossamycin was isolated FEB. 1996 from the mycelial mass by extraction with acetonitrile, separation using an HP-20ss non-functionalized resin, and then chromatography, first on silica gel and then by reversed-phase HPLC. The isolated sample was fully characterized by physico-chemical and spectroscopic methodsand shownto be identical to a sample that had been previously received from the Bristol Laboratories by HPLC(including comparison by co-injection), mass spectrometry, and NMR(in acetone-</6) spectroscopy.After the structure of ossamycin had been established by X-ray crystallography, XHand 13C NMRassignments were madeon the basis of ID comparisons with the corresponding spectra of cytovaricin and A82548Acom-bined with DEPT, COSY, TOCSY, HMQC, HMBC,

New 24-Membered Macrolides SPA-6952A and B Produced by Streptomyces sp.

“…1. Compounds 1 and 2 also bear close resemblance to ossamycin [2] and NK154183A and B [3], which have been reported from Streptomyces spp.…”

“…In screening for biologically active compounds from microbial sources, two new 24-membered macrolides, SPA-6952A (1) and B (2) (Fig. 1), were isolated from the fermentation broth of Streptomyces sp.…”

Association of Streptomyces community composition determined by PCR-denaturing gradient gel electrophoresis with indoor mold status

“…A further reason for the study of streptomycetes in the indoor environment is their production of secondary metabolites, with biological activities including antimicrobial, antitumor, immunosuppressive, antinflammatory, and cytotoxic properties, among others. In vitro and in vivo studies have demonstrated the toxic and inflammatory potential of some Streptomyces species, which makes airborne streptomycetes relevant to human health (Andersson et al 1998; Hirvonen et al 1997; Jussila et al 1999; Jussila et al 2003; Kirst et al 1996). Secondary metabolites produced by streptomycetes have been shown to frequently co-occur with mycotoxins in moisture-damaged buildings (Täubel et al 2011).…”

ATP Synthase and the Actions of Inhibitors Utilized To Study Its Roles in Human Health, Disease, and Other Scientific Areas

“…ossamyceticus (209,359). Ossamycin inhibits both the ATPase and oxidative phosphorylation activities of mitochondrial ATP synthase (150,423).…”