Seven new macrolides having a 12-membered ring, which we termed pladienolides, were isolated from the fermentation broth of Streptomyces platensis Mer-11107. Six of the seven pladienolides inhibited hypoxia-induced reporter gene expression controlled by human VEGF promoter with IC50 values of 0.0018-2.89μM. They also demonstrated growth-inhibitory activity against U251 human glioma cells in vitro. Pladienolides are highly potent inhibitors of both hypoxia signals and cancer cell proliferation, and thus may be useful as antitumor agents.
In the course of our screening using fermented broth from soil microorganisms, novel metabolites (pladienolides), possessing inhibitory activity against vascular endothelial growth factor (VEGF) expression and cancer cell proliferation, were isolated from Streptomyces platensis Mer-11107. Pladienolides A (1), B (2), C (3), D (4), E (5), F (6), and G (7) were found to be novel 12-membered macrolides by spectroscopic studies including 1H, 13C NMR, HMQC, HMBC, and NOE experiments. Pladienolides are unusual 12-membered macrolides having a long side chain at the carbon that bears a lactone oxygen.
We have discovered seven novel 12-membered macrolides, pladienolides A to G, from Streptomyces platensis Mer-11107, with pladienolide B the most potently inhibiting hypoxia induced-VEGF expression and proliferation of the U251 cancer cell line. A growth inhibitory study using a 39-cell line drug-screening panel demonstrated that pladienolide B has strong antitumor activities in vitro. A COMPARE analysis reveals that it has a unique antitumor spectrum that sets it apart from anticancer drugs currently in clinical use. This result suggests that pladienolide B has a novel mechanism of action. A series of xenograft studies were conducted to evaluate the in vivo potency of pladienolides. Pladienolide B extensively inhibited tumor growth in xenograft models. In the most sensitive model, using BSY-1 xenografts, tumors were completely regressed by administration of pladienolide B. For the reason of their novel mechanism of action and excellent in vivo efficacy, pladienolides appear to have major potential for use in cancer treatment.
In the search for strains producing antifungal compounds, a new tetraene macrolide CE-108 (3) has been isolated from culture broth of Streptomyces diastaticus 108. In addition, the strain also produces the previously described tetraene rimocidin (1) and also the aromatic polyketide oxytetracycline. Both tetraene compounds, structurally related, are produced in a ratio between 25 to 35% (CE-108 compared to rimocidin), although it can be inverted toward CE-108 production by changing the composition of the fermentation medium. This paper deals with the characterization of the producer strain, fermentation, purification, structure determination and biological properties of the new macrolide tetraene CE-108.
Three new antibiotics, vanillobiocin, isovanillobiocin and declovanillobiocin, were isolated from the culture broth of a cloQ-defective mutant of the clorobiocin producer Streptomyces roseochromogenes, which is blocked in the biosynthesis of the prenylated 4-hydroxybenzoic acid moiety of clorobiocin. Spectroscopic analysis showed that the isolated compounds were similar to clorobiocin, but contained vanillic acid as the acyl component instead of the prenylated 4-hydroxybenzoic acid present in clorobiocin. Isovanillobiocin differs from vanillobiocin by the position of the pyrrole unit attached to the sugar moiety of the antibiotic. Declovanillobiocin lacks the chlorine atom at the aminocoumarin ring. All three compounds had lower antibiotic activity against Bacillus subtilis than clorobiocin.
GE 23077 factors A1, A2, B1 and B2 are novel antibiotics isolated from fermentation broths of an Actinomadura sp. strain. GE23077 antibiotics are cyclic peptides, which inhibit Escherichia coli RNA polymerase at nM concentrations. Both rifampicin-sensitive and rifampicin-resistant polymerases are inhibited, whereas E. coli DNA polymerase and wheat germ RNA polymerase are substantially not affected. In spite of the potent activity on the enzyme, the antibiotics generally show poor activity against whole cell bacteria. The spectrum of activity is restricted to Moraxella catarrhalis, including clinical isolates, with partial activity against Neisseria gonorrhoeae and Mycobacterium smegmatis.
A-factor(2-isocapryloyl-3R-hydroxymethyl-γ-butyrolactone) acts as a microbial hormone that induces morphological development and secondary metabolism in Streptomyces griseus. A diffusible yellow pigment is produced by S. griseus in an A-factor-dependent manner under phosphate depletion. Detailed analysis of the pigment production by S. griseus cultivated in minimal liquid medium containing different concentrations of phosphate showed that the pigment was actively produced in the presence of low concentrations of phosphate and the production of the pigment was completely repressed in the presence of 2.5mM KH2PO4. HPLC analysis of the culture supernatant showed that the pigment consisted of two major, structurally related compounds and they were produced at different ratios depending on the concentration of phosphate in the medium. The structures of the two major compounds, designated as grixazone A and B, were determined by spectroscopic analyses as 1-[[2-(acetylamino)-2-carboxyethyl]thio]-2-amino-3-oxo-8-formyl-3H-phenoxiazine and 1-[[2-(acetylamino)-2-carboxyethyl]thio]-2-amino-3-oxo-8-carboxyl-3H-phenoxiazine, respectively. Grixazone A was a novel compound, although grixazone B was reported in a patent as a parasiticide produced by Streptomyces sp. DSM3813.
The fragmentation of δ-lactones, particularly triketide lactones, has been studied to provide information on the behavior of polyketides under atmospheric pressure ionization mass spectrometry (API-MS). The principal fragmentation patterns of triketide lactones are characterized by two sequential dehydrations followed by loss of CO to give hydrocarbon fragments. A particular goal of this study was an understanding of the origins of the two water molecules from the dehydrations. 18O- and 2H-isotope labeling experiments with δ-valerolactone suggest a mechanism for lactone fragmentation in which ionization by proton transfer is followed by rapid equilibration of ring-opened and ring-closed forms, which results in exchange of the ionizing proton into the hydrocarbon framework of the compound and randomization of the oxygens of the lactone. Subsequent fragmentation primarily involves sequential loss of water and CO. Similar experiments with the more complex triketide lactones show that their mass spectra share common features with that of δ-valerolactone, together with an additional water loss from the 3-hydroxyl group.