sordaricin and sordarin

Microbial transformation is known to be one of promising options to add functional groups such as a hydroxyl moiety to active base compounds to generate their derivatives. Sordaricin, a diterpene aglycone of the natural product sordarin, is an antifungal agent to selectively inhibit fungal protein synthesis by stabilizing the ribosome/EF-2 (elongation factor 2) complex. We screened actinomycetes to catalyze hydroxylation of sordaricin on the basis that the hydroxyl moiety would make it easier to generate derivatives of sordaricin. As a result of the screening, 6-hydroxylation of sordaricin was found to be catalyzed by Lentzea sp. 7887. We found that the cytochrome P450 inhibitor metyrapone inhibited this reaction, suggesting that a cytochrome P450 may be responsible for the biotransformation. As a next step, we cloned multiple cytochrome P450 genes, one of which were named P450Lent4B11, using degenerate PCR primers. The expressed cytochrome P450 derived from the P450Lent4B11 gene provided a different absorbance spectrum pattern from original one when it was incubated with sordaricin. Moreover, in cell-free conditions, the corresponding cytochrome P450 displayed the 6-hydroxylation activity toward sordaricin. Taken together, these results indicate that P450Lent4B11, derived from Lentzea sp. 7887, should be responsible for catalyzing 6-hydroxylation of sordaricin.

Topics: Actinomycetales; Antifungal Agents; Biotransformation; Cloning, Molecular; Cytochrome P-450 Enzyme System; Diterpenes; Fungi; Genes, Bacterial; Hydroxylation; Indenes; Metyrapone; Oxidation-Reduction

Six new sordarin tetracyclic diterpene glycosides, moriniafungins B-G (

Topics: Ascomycota; Dioxolanes; Diterpenes; Glycosides; Indenes; Molecular Structure; Spectrum Analysis

The first total synthesis of (-)-sordarin (1) was accomplished exploiting the following key reactions: (i) Ag(I)-catalyzed oxidative radical cyclization of a cyclopropanol derivative leading to a bicyclo[5.3.0]decan-3-one skeleton; (ii) Pd(0)-catalyzed intramolecular allylation reaction resulting in the entire strained bicyclo[2.2.1]heptan-2-one framework of sordaricin (2); (iii) selective dihydroxylation of terminal alkenes by the combined use of OsO(4) and PhB(OH)(2); and (iv) beta(1,2-cis)-selective glycosidation via a 1,3-anchimeric assistance from a 4-methoxybenzoyl group.

Topics: Biochemistry; Diterpenes; Indenes; Molecular Structure; Stereoisomerism

Rabbit pellets collected from the field were colonized by Podospora pleiospora at the exclusion of other coprophilous fungi, suggesting antibiosis. In liquid culture, P. pleiospora produced sordarin (1); sordarin B (2), a new compound in which sordarose is replaced by rhamnose; hydroxysordarin (3); and sordaricin (4). The major compounds 1 and 2 exhibited minimum inhibitory concentrations of 0.5-2.5 microg ml(-1) against the yeasts Nematospora coryli and Sporobolomyces roseus, but showed little or no activity against bacteria or coprophilous filamentous fungi. In liquid culture, the production of 1 and 2 together amounted to 2.7 microg ml(-1), whereas in rabbit dung only 1 was produced at a similar concentration (2.3 microg g(-1) fresh weight). The biosynthesis of these substances was unaffected by the presence of inoculum of other fungi tested (Sporobolomyces roseus or Penicillium claviforme) in liquid culture or on dung. Sordarin-type natural products are therefore synthesized by P. pleiospora at sufficiently high concentrations to account for antibiosis against yeasts, but not against filamentous fungi.

Topics: Animals; Antibiosis; Culture Media, Conditioned; Diterpenes; Indenes; Manure; Microbial Sensitivity Tests; Podospora; Protein Synthesis Inhibitors; Rabbits; Rhamnose; Soil Microbiology; Stereoisomerism; Yeasts

Sordarin (1) was converted to 5 and 6, which showed potent antifungal activity against yeast. A series of C1-C9 alkyl side-chain derivatives was prepared, from which it was found that the optimal activity occurred with C5. A comparison of side chains with different unsaturation showed that the cis-alkene was the most active. This result suggested that the folding of the side chains might be crucial for the optimal activity.

Topics: Antifungal Agents; Diterpenes; Indenes; Indicators and Reagents; Microbial Sensitivity Tests; Molecular Conformation; Saccharomyces cerevisiae; Structure-Activity Relationship