Metabolic products of microorganisms. 261. Obscurolides, a novel class of phosphodiesterase inhibitors from streptomyces. I. Production, isolation, structural elucidation and biological activity of obscurolides A1 to A4.

Abstract

A novel class of butyrolactones, namedobscurolides, was isolated from the culture nitrate of Streptomyces viridochromogenes by chemical screening methods. The structural elucidation of the obscurolides Ai to A4 (1~4) is described. The carboxy group of the 4-aminobenzoic acid moiety of obscurolide At (1) is reduced in the other compounds. The isolated natural products have been proved to be diastereomeric mixtures by a partial racemization at C-7 which belongs to an allylic alcohol system. The obscurolides showeda weakinhibitory activity against calcium/calmodulindependent and independent phosphodiesterases from bovine.Chemical screening is an efficient method for detecting secondary metabolites of microorganism with different types of structures and biological activities2~4). In the course of our program we have discovered the obscurolides, excreted into the culture broth of Streptomyces viridochromogenes (strain Tii 2580), due to the remarkable yellow color on silica gel TLCplates, which is obtained after staining with Ehrlich's reagent. The purified compounds,namedobscurolides, turned out to be inhibitors of cyclic AMP phosphodiesterase. In this paper we describe the isolation, characterization and structural elucidation of the obscurolides Ax to A4, which were identified as novel butyrolactone derivatives5'6).The following paper is engaged in the description of further minor compoundsof the natural obscurolide complex7). Fermentation and IsolationFermentation of Streptomyces viridochromogenes Tii 2580 was carried out in a mediumcontaining t Seeref1.

The streptazolin- and obscurolide-type metabolites from soil-derivedStreptomyces albonigerYIM20533 and the mechanism of influence of γ-butyrolactone on the growth ofStreptomycesby their non-enzymatic reaction biosynthesis

“…The congurations (3S, 4R) of streptalbonin A at C-3 and C-4 and trans orientation at C-5 and C-6 were determined by comparing the NMR spectrum with those for other obscurolides and pseudonocardides also found in actinomyces and their biogenesis. 15,19 Streptalbonin A exists in two diastereomers at C-7 just as the obscurolide A 2 reported in previous work. 15 The conguration of C-10 0 of compound 1 was determined as R by comparing the NMR and optical rotation with those for (R)-2-hydroxy-5-phenylpent-4-en-3-one formed by microorganism enzymes.…”

“…The 1 H and 13 C NMR spectroscopic analysis, including DEPT, clearly showed two methyls, one methylene, twelve methines, two olenic quaternary carbons, and two carbonyl carbons, which indicated the skeleton of obscurolide. 15 An additional pentanone should be substituted at the benzene ring, which was conrmed by the COSY correlations between H-7 0 and H-8 0 , H-10 0 and H-11 0 , and the HMBC correlations from H-11 0 to C-9 0 and C-10 0 ; H-7 0 and H-8 0 to C-9 0 ; and H-7 0 to C-3 0 and C-5 0 . Compound 1 has an unprecedented skeleton with a pentanone substituted at the benzene ring in obscurolide-type compounds.…”

“…13,14 Obscurolides, a series of butyrolactone derivatives produced by Streptomyces viridochromogenes (strain Tü 2580), present weak inhibitory activity against phosphodiesterases. 15,16 g-Butyrolactones play an autoregulation role in antibiotic production and differentiation for many members of the genus Streptomyces by modulating the DNA binding activity of cognate receptor proteins. 17 Novel butyrolactones as signaling molecules should be involved in many functional aspects in microbial life, which would be useful for synthetic biology.…”

Dimethyl [(2R,3R,5S)‐5‐phenylmorpholine‐2,3‐diyl]diacetate as a Designer Substrate in the Syntheses of Important Heterocyclic Scaffolds

“…Compound 3 or its open chain analogues b-amino-g-hydroxy carboxylates are active components of many biologically active natural products, such as antifungal/antibiotic peptides [16] and antimalarial alkaloids, [17] as well as active pharmaceuticals, such as gastroprotective drugs [18] and inhibitors of phosphodiesterase [19] and HIV-1 protease. [20] Apart from being associated with biological as well as pharmaceutical activities, this structural subunit is also used in preparing functionalized b-amino acids, [21] oxazolidinones, [22] and aziridines.…”

Paeciloquinones A,B,C,D,E and F: New Potent Inhibitors of Protein Tyrosine Kinase Produced by Paecilomyces carneus. II. Characterization and Structure Determination.

“…According to their UV and visible spectra these 7 components were closely related. One product could be identified as versiconol (7), a fungal metabolite which had previously been isolated from a strain of Aspergillus versicolor2) and from cultures of an Aspergillus parasiticus treated with dichlorvos3).…”