Natural and semisynthetic azaphilones as a new scaffold for Hsp90 inhibitors.

A series of mold metabolites of Ascomycetes, structurally belonging to the class of azaphilones, were found to inhibit the heat shock protein Hsp90. In particular, bulgarialactone B was tested for its binding to Hsp90 using surface plasmon resonance and limited proteolysis assays and for its effects on Hsp90 client proteins expression in a series of human tumor cell lines. This compound showed high affinity for Hsp90, interacting with the 90-280 region of the N-terminal domain and down-regulated the Hsp90 client proteins Raf-1, survivin, Cdk4, Akt, and EGFR.

Microbial transformations of the taxan ring of 10-DAB by some strains of the fungus Curvularia lunata: formation of the bis-abeotaxanes wallifoliol and 4-deacylwallifoliol.

The fermentation of 10-deacetylbaccatine III (10-DAB) (1) with Curvularia lunata afforded 4-deacylwallifoliol (4) and wallifoliol (5), the only natural taxoid with the unusual 5/6/6/6/4 ring system. The X-ray structure of compound 4 is reported. The skeletal rearrangements induced by the microbial enzymatic systems are also discussed.

Anomalous microbial transformations on the taxane ring of 10-DAB by a strain of the fungus Curvularia lunata: transbenzoylation, transacetylation, and opening of the oxetane ring.

The fermentation of 10-deacetylbaccatin III (10-DAB) (1) with Curvularia lunata afforded the taxane hemiacetals 2a and 3, characterized by extensive structural modification, including C-2 to C-1 transbenzoylation, oxidation of the C-2 hydroxyl, formation of a C-9/C13 hemiacetal, epimerization at C-10, and migration of the endocyclic double bond to an exocyclic location. In compound 3, an acetate-assisted opening of the oxetane ring was also observed.

Acremine G, dimeric metabolite from cultures of Acremonium byssoides A20.

A new dimeric fungal metabolite, racemic acremine G, was isolated from cultures of the fungus Acremonium byssoides A20, along with the known acremines A-F. Its structure was elucidated by NMR spectroscopy and X-ray crystallography. A possible biosynthetic pathway is discussed.

Microbial transformation of spirolaxine, a bioactive undecaketide fungal metabolite from the basidiomycete Sporotrichum laxum.

Incubation of (+)-spirolaxine (= (3R)-5-hydroxy-7-methoxy-3-{5-[(2R,5R,7R)-2-methyl-1,6-dioxaspiro[4.5]dec-7-yl]pentyl}-2-benzofuran-1(3H)-one; 1a) with Bacillus megaterium afforded two new mono- and one new dihydroxylated metabolite(s), all OH groups being introduced on the non-activated six-membered ring. In contrast, exposure of 1a to Cunninghamella echinulata gave rise to hydroxylation on the five-membered ring of the parent structure.

Absolute configuration of sporotricale and structure of 6-hydroxysporotricale.

The absolute configuration of the two stereocenters of (+)-sporotricale (2a), a bioactive phthalide secondary metabolite, was determined through circular dichroism and by applying Mosher's method. The structure of 6-hydroxysporotricale (2c), isolated from cultures in vitro of Sporotrichum laxum, was also elucidated.

Synthesis of (+)-spirolaxine methyl ether.

A short and efficient synthesis of (+)-spirolaxine methyl ether, a metabolite of the fungus Sporotrichum laxum with inhibitory activity against Helicobacter pylori, is described. The synthesis has been carried out by a Prins cyclization, to obtain the [6,5]-spiroketal system, and a Wadsworth-Emmons condensation, applied for the installation of the polymethylene chain on the phthalide moiety.

Enhancement of a pentacyclic tyrosine kinase inhibitor production in Cladosporium cf. cladosporioides by Cladosporol.

The binaphthyl derivative cladosporol 3 was supplied from 60 to 200 mg l(-1) to shaken cultures of Cladosporium cf. cladosporioides. Compared to blank, fungal biomass was not affected by adding cladosporol till 100 mg l(-1): it rather increased at higher ratios between 150 and 200 mg l(-1).

Secondary mould metabolites of Cladosporium tenuissimum, a hyperparasite of rust fungi.

Investigation of the extracts of a culture of Cladosporium tenuissimum, a known hyperparasite of several rust fungi, gave rise to the isolation of cladosporols B-E (2-5). Their structure and stereochemistry were elucidated on the basis of 1H and 13C NMR evidence and CD measures. Cladosporols 1-5 were active in inhibiting the urediniospore germination of the bean rust agent Uromyces appendiculatus.

A new azoxyalkene from a strain of an actinomadura-like fungus.

A new proximal alpha,beta-( cis)-unsaturated azoxyalkene (1) was produced by a fungal strain named A7, identified as Actinomadura sp., isolated from apricot (Prunus armeniaca) roots. Compound 1 was isolated together with the polyene macrolide fungichromine, and its structure and geometry were established mainly by UV, MS and 1H- and 13C-NMR mono-dimensional and two-dimensional experiments.

Cryphonectric acid and other minor metabolites from a hypovirulent strain of Cryphonectria parasitica.

Investigations carried out on secondary metabolites produced in culture by a hypovirulent strain of Cryphonectria parasitica allowed the isolation of several compounds which were characterized by NMR analysis and derivatization reactions. The most abundant metabolite was a new compound, called cryphonectric acid (1). Other metabolites were diaporthin, the only known phytotoxic compound isolated from both virulent and hypovirulent strains of C.