New tricyclic geldanamycin analogues from an engineered strain of Streptomyces hygroscopicus JCM4427

Two tricyclic geldanamycin analogues, DHQ5 (1) and DHQ6 (2), were produced by a combinatorial mutant (AC15) contained a site-directed mutagenesis on the geldanamycin polyketide synthase (PKS) gene with inactivation of the post-PKS tailoring genes (gel7) of Streptomyces hygroscopicus JCM4427. The structural diversity of tricyclic geldanamycin analogues is due to the formation of unusual additional rings, which are formed by alkylation of the C-21 position by C-12 in DHQ5 (1) and by electrophilic addition of the C-15 hydroxyl group to the double bond (C-8-C-9), which leads to the migration of the double bond (to C-7-C-8) and the elimination of a carbamoyloxy group in DHQ6 (2).     

Bioactive butenolides from Streptomyces antibioticus TÜ 99: absolute configurations and synthesis of analogs

The four furanones (butenolides) 1-4, which had been isolated from the fermentation broth of Streptomyces antibioticus TÜ 99 and in preliminary tests had been shown to be biologically active, were synthesized by reaction of the readily available furanones 9 or 16 with 2-methylpropanal or 2-methylbutanal. In addition, a series of analogs was prepared in a similar way from 16 using different aldehydes. The hitherto unknown absolute configurations of the natural products 1-4 as well as those of all the analogs prepared were determined with Mosher's NMR method and/or X-ray crystallography. Some of the compounds synthesized proved to be active in the quorum sensing system of Chromobacterium violaceum.     

Recent developments on the fluorinase from Streptomyces cattleya

This is a summary of a lecture presented at the 100th Anniversary, Moissan Symposium in Paris on Friday, 10 November 2006. The lecture highlighted recent developments on the enzyme structure, mechanism and biotransformation prospects of the fluorinase enzyme identified in 2002 from the bacterium Streptomyces cattleya. Over-expression of the enzyme has allowed it to be used as a catalyst for ¹⁸F-incorporation during the synthesis of potential ligands for positron emission tomography (PET) applications.     

New polyesters from Talaromyces flavus

Six new polyesters, talapolyesters A–F (1–4, 14, and 16), together with 11 known ones 15G256ν (5), 15G256ν-me (6), 15G256π (7), 15G256β-2 (8), 15G256α-2 (9), 15G256α-2-me (10), 15G256ι (11), 15G256β (12), 15G256α (13), 15G256α-1 (15), and 15G256ω (17), were isolated from the wetland soil-derived fungus Talaromyces flavus BYD07-13, and their structures were determined by NMR and MS spectroscopic data. Among them, 1–4 and 16 were assembled in a different manner from that of the known 256 polyesters. All the polyesters are composed of (R)-2,4-dihydroxy-6-(2-hydroxypropyl)benzoic acid and (R)-3-hydroxybutyric acid/(S)-3,4-dihydroxybutyric acid residues. The absolute configurations of the residues were determined by alkaline hydrolysis. The cytotoxicity against five tumor cell lines of these compounds was examined, and a tight structure–activity relationship is proposed.     

Five new derivatives of nonactic and homo-nonactic acids from Streptomyces globisporus

In addition to the known compounds of the type of nonactic and homononactic acids and their lactones, dilactones and tetralactones, five new compounds, namely homononactyl-nonactoate, a dilactone consisting of nonactic and homononactic acids and three cyclic trimers with nonactic and homononactic acids, were isolated from a strain of Streptomyces globisporus. Their structures, including the absolute configurations of the hydroxyl and methyl groups, were determined by extensive spectroscopic techniques such as UV, IR, MS, 1D and 2D NMR.     

Dolastanes from the brown alga Dilophus spiralis: absolute stereochemistry and evaluation of cytotoxicity

Five new dolastanes (1-5) were isolated from the brown alga Dilophus spiralis. The structural elucidation of the isolated compounds and the assignment of relative stereochemistry were based on analyses of their spectroscopic data. The structure proposed for 1 was confirmed by single crystal X-ray diffraction analysis, whereas its absolute stereochemistry was determined using the modified Mosher's method. The cytotoxicity of 1-4 was evaluated against seven cell lines.     

Antimicrobial tunicamycin derivatives from the deep sea-derived Streptomyces xinghaiensis SCSIO S15077

Abstract

Tunicamycin E (1), featuring a methyl substitution at C-10′, was isolated from marine-derived Streptomyces xinghaiensis SCSIO S15077 originated from the South China Sea sediment together with six known compounds, tunicamycin B (2), tunicamycin X (3), tunicamycin A (4), streptovirudin D₂ (5), tunicamycin C (6), and tunicamycin C₃ (7). The structure of compound 1 was elucidated by detailed spectroscopic data analyses. All the compounds exhibited strong to moderate antibacterial activity against Gram-positive bacteria Bacillus thuringiensis BT01 and B. thuringiensis W102 with MIC values ranging from 0.008 to 2 μg/mL. Moreover, compounds 1–7 exhibited moderate antifungal activity against Candida albicans ATCC 96901 and C. albicans CMCC (F) 98001 with MIC values ranging from 2 to 32 μg/mL. This is the first report that tunicamycins exhibit antimicrobial activities against B. thuringiensis, C. albicans CMCC (F) 98001 and a fluconazole resistant strain C. albicans ATCC 96901.     

The absolute stereochemistry of anachelins, siderophores from the cyanobacterium Anabaena cylindrica

The absolute stereochemistry of anachelins (1 and 2), siderophores isolated from the freshwater cyanobacterium Anabaena cylindrica, was determined via the application of Boc-phenylglycine and Mosher's method. Consequently, it was revealed that a 1,1-dimethyl-3-amino-1,2,3,4-tetrahydro-6,7-dihydroxyquinolinium unit (Dmaq) has 3S (eq.) configuration, and a 6-amino-3,5,7-trihydroxyheptanoic acid unit (Atha) has 3R, 5S, 6S configuration. The 6S configuration of Atha suggested that l-Ser was a biosynthetic precursor of Atha.     

Pseudoverticin, a novel benzoquinone-derived ansamycin antibiotic obtained as new cell cycle inhibitor from Streptomyces pseudoverticillus YN17707

Pseudoverticin (1), a novel benzoquinone-derived ansamycin antibiotic showing cell cycle inhibitory activity, was isolated from the fermentation broth of Streptomyces pseudoverticillus YN17707 together with the known ansamycin antibiotic geldanamycin (2) through a bioassay-guided separation procedure. The structure of 1 was elucidated by spectroscopic methods, being characterized by an ansa bridge the same as that in 2 and a novel benzoquinone-derived moiety. Pseudoverticin (1) arrested the cell cycle of tsFT210 cells at the G0/G1 phase with the MIC value of 2.5 μM.     

Additional cytotoxic substances isolated from the sponge-derived Gymnascella dankaliensis

A continuous investigation of secondary metabolites produced by the sponge-derived fungus, Gymnascella dankaliensis, has yielded a new polyketide tyrosine derivative, dankastatin C (3) and the known steroid, demethylincisterol A₃ (4), which was originally found from a Homaxinella marine sponge. The stereostructure of the new compound has been determined based on the analysis of 1D and 2D NMR data. Dankastatin C (3) showed potent cell growth inhibitory activity against the murine P388 cell line.     

New cytotoxic sesquiterpenes from the red algae Laurencia obtusa and Laurencia microcladia

Three new sesquiterpenes (1-3), along with five known (5-9), were isolated from the organic extract of the red alga Laurencia obtusa, collected from the coastal rocks of Serifos in the Aegean Sea. A new dimeric sesquiterpene of the cyclolaurane-type (4) along with four previously reported (7, 10-12) metabolites, were isolated from the extract of Laurencia microcladia, collected at Chios island in the North Aegean Sea. The structures and the relative stereochemistry of the compounds are proposed on the basis of their spectral data. The cytotoxicity of the isolated metabolites was evaluated against several cell lines including human tumor cell lines.     

Euryjanicin A: a new cycloheptapeptide from the Caribbean marine sponge Prosuberites laughlini

A new proline-containing cycloheptapeptide, euryjanicin A (1), has been isolated from the marine sponge Prosuberites laughlini indigenous to Puerto Rico, and its structure established by an X-ray crystal structure determination. The absolute configuration of each amino acid residue was determined by Marfey’s method.     

Structures and absolute stereochemistry of nipponallene and neonipponallene, new brominated allenes from the red alga Laurencia nipponica

Two new natural brominated allenes named as nipponallene 1 and neonipponallene 2 were isolated from the red alga Laurencia nipponica, collected near the Russian shore of the Sea of Japan (Troitsa Bay). The structures and absolute stereochemistry of 1 and 2 were elucidated using NMR spectroscopy, chemical transformations, modified Mosher’s method and on the basis of biogenetic understanding.     

Capnosane-type cembranoids from the soft coral Sarcophyton trocheliophorum with antibacterial effects

Nineteen new cembranoids with unusual capnosane skeleton named trocheliophols A–S (1–19) together with four known analogues were isolated from the Chinese soft coral Sarcophyton trocheliophorum. Their structures were determined on the basis of extensive spectroscopic (IR, MS, 1D and 2D NMR) analysis, in addition to the modified Mosher's method, CD and X-ray diffraction for the configuration assignments. The inhibitory effects of the isolated compounds against inflammation-related NF-κB and bacterial pathogens were evaluated. Compounds 8, 9 and 19 exhibited potent inhibitory effects against phytopathogens and human disease-related Gram positive and negative bacteria, while the preliminary structure–activity relationship is discussed.     

The nebramycin aminoglycoside profiles of Streptomyces tenebrarius and their characterization using an integrated liquid chromatography-electrospray ionization-tandem mass spectrometric analysis

The development of an efficient analytical protocol for the reliable identification of the biosynthetic intermediates found in microbial cultures, which usually produce complex intermediates of the metabolites of interest, is both challenging and essential for further studies into gene-to-metabolite networks. A simple and highly selective method for detecting the biosynthetic intermediates involved in the aminoglycosidic nebramycin pathway of Streptomyces tenebrarius was developed and validated. Cleanup utilizing a solid-phase extraction (OASIS MCX SPE) technique provides a simple and reproducible method for extracting the nebramycin factors from a fermentation broth. The separation of each factor through a reversed-phase C₁₈ column using an ion-pairing reagent allowed the simultaneous profiling of the aminoglycosides. By employing the authentic tobramycin spiked into a blank fermentation medium, the combined use of acid extraction, OASIS MCX SPE cleanup, and HFBA (heptafluorobutyric acid)-mediated chromatographic separation coupled with electrospray ionization-tandem mass spectrometry (ESI-MS/MS) detection was proven to be sufficiently accurate and reliable to analyze the nebramycin factors produced in a culture broth. The detection limit of tobramycin spiked in the culture broth was approximately 1.8 ng mL⁻¹. The mean recovery ranged from 89 to 92%, the intra- and inter-day precision (RSD) was <6% and their accuracy ranged from 88 to 93%. A total of nine nebramycin factors including apramycin, 6″-O-carbamoylkanamycin B, 6″-O-carbamoyltobramycin, 3′-hydoxyapramycin, tobramycin, kanamycin B, NK-1012-1, nebramine, and neamine were identified. This is the first report on the integrated LC-ESI-MS/MS characterization of a wide range of nebramycin factors from a bacterial fermentation broth.     

Mevashuntin, a novel metabolite produced by inhibition of the mevalonate pathway in Streptomyces prunicolor

Inhibition of the mevalonate pathway by an HMG-CoA reductase inhibitor, mevalotin, in Streptomyces prunicolor possessing both mevalonate and MEP pathways resulted in the production of a new metabolite mevashuntin that consisted of conjugated thiazolone and pyranonaphthoquinone moieties.     

Lyconadins C and F, new Lycopodium alkaloids from Lycopodium complanatum

New Lycopodium alkaloids, lyconadins C (1) and F (2), were isolated from the club moss Lycopodium complanatum. Lyconadin C (1) is a new C₁₆N₂-type Lycopodium alkaloid possessing unique fused-tetracyclic ring system consisting of a cycloheptene ring fused to a decahydroquinoline and pyridone rings. Lyconadin F (2) possesses a primary amide moiety in its molecular, which is the first example of Lycopodium alkaloids. Biogenetically, lyconadins C (1) and F (2) might be related to lyconadins A (4) and B (5). The structures and relative stereochemistry of 1 and 2 were elucidated on the basis of spectroscopic data. The absolute stereochemistry of 2 was elucidated by chemical correlations with lyconadin B (5) through hemiaminal form of lyconadin F (3).     

Synthesis and elucidation of absolute stereochemistry of salaprinol, another thiosugar sulfonium sulfate from the ayurvedic traditional medicine Salacia prinoides

Synthesis and elucidation of absolute stereochemistry of salaprinol (3) isolated from the root and stems of Salacia prinoides, which has been used for the treatment of diabetes in India, Sri Lanka, and Southeast Asia countries, is described. Compound 3 and its 2′-epimer, epi-salaprinol (epi-3) were synthesized via the coupling reaction of a cyclic sulfate, 2-O-benzylglycerol 1,3-cyclic sulfate (5), with a thiosugar, 1,4-dideoxy-1,4-epithio-d-arabinitol (6), as the key reaction, and S configuration of the asymmetric center in the side chain of 3 was elucidated by the X-ray crystallographic analysis.     

Seven new prenylated indole diketopiperazine alkaloids from holothurian-derived fungus Aspergillus fumigatus

Seven new prenylated indole diketopiperazine alkaloids, including compound 1, 3 spirotryprostatins C-E (2-4), 2 derivatives of fumitremorgin B (5 and 6), and 13-oxoverruculogen (7), have been isolated from the holothurian-derived fungus Aspergillus fumigatus, along with 12 known ones (8-19). The structures of the new compounds were determined on the basis of extensive spectroscopic data and amino acid analysis. All new compounds were evaluated for their cytotoxic activities on MOLT-4, A549, HL-60, and BEL-7420 cell lines by the MTT and SRB methods.     

The first total synthesis and absolute stereochemistry of plakortone G from the Jamaican sponge Plakortis sp.

Total synthesis of plakortone G (1), a secondary metabolite of the Jamaican sponge Plakortis sp., was successfully achieved. The absolute configuration of this molecule was determined by comparison of the synthetic diastereomers with reported data to possess the (4R,8R)-configuration 14.