Gianluca Nasini

Screening of the genus Cercospora for secondary metabolites

Abstract Screening of 61 species of Cercospora grown on a potato-agar medium showed the presence of the phytotoxin cercosporin in 24 of them, and of dothistromin in 8. Some strains of C. beticola produce a yellow phytotoxin (CBT). The new metabolites cercosporin esters, ligustrone A, B, C, taiwapyrone, 3-methoxy-2,5,7-trihydroxy-1,4-naphthaquinone, cis -4,6-dihydroxymellein and ( − )-11-acetyldehydrocurvularin were isolated besides the known cynodontin, ( − )-dehydrocurvularin, (+ )-mellein and cis -3 S ,4 S -4-hydroxymellein.

Structures of melleolides B-D, three antibacterial sesquiterpenoids from Armillaria mellea

Abstract The structures of melleolides B-D, three new protoilludene sesquiterpenoid O-methylorsellinates isolated from a culture of Armillaria mellea , have been elucidated on the basis of chemical and spectral data.

Clavilactones, a novel class of tyrosine kinase inhibitors of fungal origin.

Targeting of deregulated protein tyrosine kinases has been proposed as a new approach in the therapeutic intervention against pathological processes including proliferative disorders and cancer. Using a screening approach based on a comparative evaluation of antiproliferative effects in a panel of tumor cells with differential expression of protein tyrosine kinases, three benzoquinoid macrolidic fungal metabolites produced by Clitocybe clavipes, clavilactones A, B, and D (CA, CB, and CD) and two semisynthetic derivatives of these products, diacetyl-CA and dimethyl-CA, were identified as inhibitors of protein tyrosine kinases. Naturally occurring CA, CB, and CD showed inhibitory activity in kinase assays against the Ret/ptc1 and epidermal growth factor receptor (EGF-R) tyrosine kinases, while being less effective against the v-Abl tyrosine kinase and p34(cdc2) serine/threonine kinase (IC(50) 2.8, 5.5, 81.3, and 128 microM respectively, for the most potent compound CD). CB was shown to be a non-competitive inhibitor of EGF-R with respect to ATP or poly(Glu(6)Ala(3)Tyr). CD also preferentially inhibited the growth of A431 cells, which overexpress a constitutively active EGF-R, as opposed to IGROV-1 and SKOV-3 cells, which express low levels of the receptor. Further, EGF-R was shown to be a target for clavilactones in A431 cells, since EGF-induced receptor autophosphorylation was inhibited in the presence of CB, CD, and diacetyl-CA. Both CD and diacetyl-CA displayed weak activity when administered daily (i.p.) to mice bearing ascitic A431 tumor. These findings indicate that clavilactones represent the prototypes of a new structural class of tyrosine kinase inhibitors deserving further investigation.

Metabolites of Cercospora. Taiwapyrone, an α-pyrone of unusual structure from Cercospora taiwanensis

Abstract (+)-Mellein ( 1 ), cis-3 S ,4 S -4-hydroxymellein ( 3 ), and taiwapyrone ( 4 ), a new α-pyrone, have been isolated from the mycelium of Cercospora taiwanensis , grown on potato-agar. The structure and absolute configuration of ( 3 ) and ( 4 ) have been elucidated.

Structure elucidation of clavilactone D: an inhibitor of protein tyrosine kinases

Clavilactones D and E were isolated from an agar culture of the Basidiomycetous fungus Clitocybe clavipes, and their structure was elucidated by 1H- and 13C-NMR studies. Clavilactone D is an inhibitor of tyrosine kinases.

Secondary mould metabolites. Part 47. Isolation and structure elucidation of clavilactones A–C, new metabolites from the fungus Clitocybe clavipes

Clavilactones A–C (1, 4 and 5) have been isolated from cultures of the Basidiomycetous fungus Clitocybe clavipes. Their structures and relative configurations have been deduced from 1H and 13C NMR studies, chemical reactions and single-crystal X-ray analysis of the dimethyl ether derivative 3. 1H–1H coupling constants, NOE data and molecular modelling calculations all suggest that the molecules have little conformational mobility and the conformation adopted in solution by clavilactone A 1 and dimethyl ether derivative 3 is essentially identical with that of 3 in the solid state. Clavilactones A–C exhibit antifungal and antibacterial activity and inhibit the growth germination of Lepidium sativum. A possible biogenetic origin of clavilactone A 1 is discussed.

Indole alkaloids from gambir structure of bambirtannine, oxogambirtannine and dihydrogambirtannine

Abstract On the basis of chemical and spectral evidence, the structures I, II and III were assigned to gambirtanine, dihydrogambirtannine and oxogambirtannine, three new indole alkaloids extracted from the tannin Gambir. The phenol betaine IV (neooxygambirtannine) was obtained during the workup of the extract.

Perylenequinones from cucumber seedlings infected with Cladosporium cucumerinum

Abstract The structure of cladochrome A, a perylenequinone pigment isolated from etiolated cucumber seedlings infected with fungal spores of Cladosporium cucumerinum, has been revised and established as that of a diester of 3-hydroxybutyric acid with ent-isophleichrome. Another pigment from the same source, cladochrome B, is the corresponding ester of ent-isophleichrome with 3-hydroxybutyric and benzoic acids.

The structure of roxburghines A–E, new indole alkaloids from an Uncaria Sp☆

Abstract The structural elucidation of roxburghines A–E, new diastereoisomeric indole alkaloids C 31 H 32 N 4 O 2 , isolated from the leaves and stems of an Uncaria Sp., is reported. The derivation of the skeleton ( 4 ) from two tryptamine and one monoterpenoid C 10 units is consistent with the current biogenetic theory. Tetrahydroalstonine, one isomer, and dihydrocorynantheine were also isolated.

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. Bulgarialactone B and other natural azaphilones showed antiproliferative activity in a panel of human tumor cell lines; their conversion into semisynthetic derivatives by reaction with primary amines increased the antiproliferative activity. Preliminary results indicated in vivo activity of bulgarialactone B against an ascitic ovarian carcinoma xenograft, thus supporting the therapeutic potential of this novel series of Hsp90 inhibitors.