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Microbial biotransformation of argentatin A (1), isoargentatin A (2) and argentatin C (3), the triterpenoid constituents of guayule (Parthenium argentatum) resin was conducted with Chaetomium sp. PA001, an endophytic fungus of the same plant. The experiments yielded six new products (4 – 9) formed by: (i) nucleophilic oxygenation of the 3-ketone moiety resulting in Baeyer-Villiger oxidation; (ii) lactone ring opening of these oxidation products; (iii) rearrangement of the 9(10)-cyclopropane ring; and (iv) reduction of the 3-ketone moiety. The structures of all new biotransformation products were established by detailed analysis of their spectroscopic data. None of the products exhibited any antimicrobial activity. However, the hydroxy-carboxylic acid derivative 5 of argentatin A showed weak cytotoxic activity, but improved selectivity against human breast cancer cell line MCF-7 compared to the parent compound. This constitutes the first report of microbial biotransformation of isoargentatin A and argentatin C. [Display omitted] • Biotransformation of guayule resin triterpenes was studied for value-added products. • Chaetomium sp. PA001 was selected for biotransformation after screening 16 fungi. • Six new biotransformation products were isolated and characterized. • One of the products had weak cytotoxicity with selectivity for breast cancer cells. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Secondary metabolite profile of the endophytic fungus, Anteaglonium sp. FL0768, was found to be affected by culture conditions. • Incorporation of Cu2+ enhanced production of metabolites and drastically affected the polyketide biosynthetic pathway. • The histone acetyl transferase inhibitor, anacardic acid, slightly affected the metabolite profile. • The epigenetic modifiers, 5-azacytidine and suberoyl anilide hydroxamic acid had no effect on its secondary metabolite profile. Abstract In an attempt to explore the biosynthetic potential of endosymbiotic fungi, the secondary metabolite profiles of the endophytic fungus, Anteaglonium sp. FL0768, cultured under a variety of conditions were investigated. In potato dextrose broth (PDB) medium, Anteaglonium sp. FL0768 produced the heptaketides, herbaridine A (1), herbarin (2), 1-hydroxydehydroherbarin (3), scorpinone (4), and the methylated hexaketide 9 S ,11 R -(+)-ascosalitoxin (5). Incorporation of commonly used epigenetic modifiers, 5-azacytidine and suberoylanilide hydroxamic acid, into the PDB culture medium of this fungus had no effect on its secondary metabolite profile. However, the histone acetyl transferase inhibitor, anacardic acid, slightly affected the metabolite profile affording scorpinone (4) as the major metabolite together with 1-hydroxydehydroherbarin (3) and a different methylated hexaketide, ascochitine (6). Intriguingly, incorporaion of Cu2+ into the PDB medium enhanced production of metabolites and drastically affected the biosynthetic pathway resulting in the production of pentaketide dimers, palmarumycin CE 4 (7), palmarumycin CP 4 (8), and palmarumycin CP 1 (9), in addition to ascochitine (6). The structure of the new metabolite 7 was established with the help of spectroscopic data and by MnO 2 oxidation to the known pentaketide dimer, palmarumycin CP 3 (10). Biosynthetic pathways to some metabolites in Anteaglonium sp. FL0768 are presented and possible effects of AA and Cu2+ on these pathways are discussed. [ABSTRACT FROM AUTHOR]

Abstract: The carcinogen and mutagen, 1-aminoanthracene, was efficiently metabolized by the fungal strain Beauveria bassiana ATCC 7159 to yield three new metabolites identified as 1-acetamido-5-[(4′-O-methyl-β-d-glucopyranosyl)oxy]anthracene, 1-acetamido-8-[(4′-O-methyl-β-d-glucopyranosyl)oxy]anthraquinone, and 1-acetamido-6-[(4′-O-methyl-β-d-glucopyranosyl)oxy]anthraquinone, together with 1-acetamidoanthracene and 1-acetamidoanthraquinone. Formation of these metabolites suggests that the metabolic pathways of 1-aminoanthracene in B. bassiana ATCC 7159 involve acetylation, oxidation, hydroxylation, and O-methylglucosylation. [Copyright &y& Elsevier]

Abstract: Biomimetic-type reactions of the tricyclic pyridone alkaloid, (−)-fusoxypyridone [(−)-4,6′-anhydrooxysporidinone] (1), recently encountered in an endophytic strain of Fusarium oxysporum, and (−)-oxysporidinone (2) afforded (−)-sambutoxin (3) and an analogue of 1, identified as (−)-1′(6′)-dehydro-4,6′-anhydrooxysporidinone (4), thus confirming the structure previously proposed for 1 and suggesting that 1–3 bear the same relative stereochemistry. Oxidation of 4 with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) yielded a hitherto unknown sambutoxin analogue, (−)-4,2′-anhydrosambutoxin (5). [Copyright &y& Elsevier]

Eleven withanolides including six previously undescribed compounds, 16 β -hydroxyixocarpanolide, 24,25-dihydroexodeconolide C, 16,17-dehydro-24- epi -dioscorolide A, 17- epi -philadelphicalactone A, 16-deoxyphiladelphicalactone C, and 4-deoxyixocarpalactone A were isolated from aeroponically grown Physalis philadelphica . Structures of these withanolides were elucidated by the analysis of their spectroscopic (HRMS, 1D and 2D NMR, ECD) data and comparison with published data for related withanolides. Cytotoxic activity of all isolated compounds was evaluated against a panel of five human tumor cell lines (LNCaP, ACHN, UO-31, M14 and SK-MEL-28), and normal (HFF) cells. Of these, 17- epi -philadelphicalactone A, withaphysacarpin, philadelphicalactone C, and ixocarpalactone A exhibited cytotoxicity against ACHN, UO-31, M14 and SK-MEL-28, but showed no toxicity to HFF cells. [ABSTRACT FROM AUTHOR]

Incorporation of the histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA), to a culture broth of the endophytic fungus Phoma sp. nov. LG0217 isolated from Parkinsonia microphylla changed its metabolite profile and resulted in the production of (10′ S )-verruculide B ( 1 ), vermistatin ( 2 ) and dihydrovermistatin ( 3 ). When cultured in the absence of the epigenetic modifier, it produced a new metabolite, ( S , Z )-5-(3′,4′-dihydroxybutyldiene)-3-propylfuran-2(5H)-one ( 4 ) together with nafuredin ( 5 ). The structure of 4 was elucidated by spectroscopic analyses and its absolute configuration was determined by application of the modified Mosher’s ester method. The absolute structure of (10′ S )-verruculide B was determined as 5-[(10′ S ,2′ E ,6′ E )-10′,11′-dihydroxy-3′,7′,11′-trimethyldodeca-2′,6′-dien-1′-yl]-(3 R )-6,8-dihydroxy-3-methylisochroman-1-one ( 1 ) with the help of CD and NOE data. Compound 1 inhibited the activity of protein tyrosine phosphatases (PTPs) 1B (PTP1B), Src homology 2-containing PTP 1 (SHP1) and T -cell PTP (TCPTP) with IC 50 values of 13.7 ± 3.4, 8.8 ± 0.6, and 16.6 ± 3.8 μM, respectively. Significance of these activities and observed modest selectivity of 1 for SHP1 over PTP1B and TCPTP is discussed. [ABSTRACT FROM AUTHOR]

Screening of a small library of natural product extracts derived from endophytic fungi of the Sonoran desert plants in a cell-based anti-HIV assay involving T-cells infected with the HIV-1 virus identified the EtOAc extract of a fermentation broth of Alternaria tenuissima QUE1Se inhabiting the stem tissue of Quercus emoryi as a promising candidate for further investigation. Bioactivity-guided fractionation of this extract led to the isolation and identification of two new metabolites, altertoxins V ( 1 ) and VI ( 2 ) together with the known compounds, altertoxins I ( 3 ), II ( 4 ), and III ( 5 ). The structures of 1 and 2 were determined by detailed spectroscopic analysis and those of 3 – 5 were established by comparison with reported data. When tested in our cell-based assay at concentrations insignificantly toxic to T-cells, altertoxins V ( 1 ), I ( 3 ), II ( 4 ), and III ( 5 ) completely inhibited replication of the HIV-1 virus at concentrations of 0.50, 2.20, 0.30, and 1.50 μM, respectively. Our findings suggest that the epoxyperylene structural scaffold in altertoxins may be manipulated to produce potent anti-HIV therapeutics. [ABSTRACT FROM AUTHOR]

Abstract: Recent studies have shown that novobiocin (NB), a member of the coumermycin (CA) family of antibiotics with demonstrated DNA gyrase inhibitory activity, inhibits Heat shock protein 90 (HSP90) by binding weakly to a putative ATP-binding site within its C-terminus. To develop more potent HSP90 inhibitors that target this site and to define structure–activity relationships (SARs) for this class of compounds, we have synthesized twenty seven 3-amido-7-noviosylcoumarin analogues starting from NB and CA. These were evaluated for evidence of HSP90 inhibition using several biological assays including inhibition of cell proliferation and cell cycle arrest, induction of the heat shock response, inhibition of luciferase-refolding in vitro, and depletion of the HSP90 client protein c-erbB-2/HER-2/neu (HER2). This SAR study revealed that a substantial increase in biological activity can be achieved by introduction of an indole-2-carboxamide group in place of 4-hydroxy-isopentylbenzamido group at C-3 of NB in addition to removal/derivatization of the 4-hydroxyl group from the coumarin ring. Methylation of the 4-hydroxyl group in the coumarin moiety moderately increased biological activity as shown by compounds 11 and 13. Our most potent new analogue 19 demonstrated biological activities consistent with known HSP90-binding agents, but with greater potency than NB. [Copyright &y& Elsevier]

Abstract: In an attempt to maximize production and the structural diversity of plant metabolites, the effect of growing the medicinal plant Withania somnifera under soil-less aeroponic conditions on its ability to produce withaferin A and withanolides was investigated. It resulted in the isolation and characterization of two compounds, 3α-(uracil-1-yl)-2,3-dihydrowithaferin A (1) and 3β-(adenin-9-yl)-2,3-dihydrowithaferin A (2), in addition to 10 known withanolides including 2,3-dihydrowithaferin A-3β-O-sulfate. 3β-O-Butyl-2,3-dihydrowithaferin A (3), presumably an artifact formed from withaferin A during the isolation process was also encountered. Reaction of withaferin A with uracil afforded 1 and its epimer, 3β-(uracil-1-yl)-2,3-dihydrowithaferin A (4). The structures of these compounds were elucidated on the basis of their high resolution mass and NMR spectroscopic data. [Copyright &y& Elsevier]

Abstract: Syntheses of the bacterial surfactants 6S,6S-, 9S,9S-, and 9U,9U-flavolipids confirmed the structures proposed for them from spectroscopic analysis of a flavolipid mixture and made pure flavolipids available for the first time. All three synthetic flavolipids and a straight chain analogue were found to be weakly cytotoxic and to inhibit metastatic cancer cell migration, with 9U,9U-flavolipid (the most abundant natural flavolipid) having the most activity. Biosynthetic routes to the branched side-chains of the flavolipids are suggested, and it is proposed that branched chains are employed to hinder biodegradation. [ABSTRACT FROM AUTHOR]

Abstract: The purpose of this study is to investigate the efficacy and the mechanism of Hsp90 inhibition of Withaferin A (WA), a steroidal lactone occurring in Withania somnifera, in pancreatic cancer in vitro and in vivo. Withaferin A exhibited potent antiproliferative activity against pancreatic cancer cells in vitro (with IC50s of 1.24, 2.93 and 2.78μM) in pancreatic cancer cell lines Panc-1, MiaPaCa2 and BxPc3, respectively. Annexin V staining showed that WA induced significant apoptosis in Panc-1 cells in a dose-dependent manner. Western blotting demonstrated that WA inhibited Hsp90 chaperone activity to induce degradation of Hsp90 client proteins (Akt, Cdk4 and glucocorticoid receptor), which was reversed by the proteasomal inhibitor, MG132. WA-biotin pull down assay of Hsp90 using Panc-1 cancer cell lysates and purified Hsp90 showed that WA-biotin binds to C-terminus of Hsp90 which was competitively blocked by unlabeled WA. Co-immunoprecipitation exhibited that WA (10μM) disrupted Hsp90–Cdc37 complexes from 1 to 24h post-treatment, while it neither blocked ATP binding to Hsp90, nor changed Hsp90–P23 association. WA (3, 6mg/kg) inhibited tumor growth in pancreatic Panc-1 xenografts by 30% and 58%, respectively. These data demonstrate that Withaferin A binds Hsp90, inhibits Hsp90 chaperone activity through an ATP-independent mechanism, results in Hsp90 client protein degradation, and exhibits in vivo anticancer activity against pancreatic cancer. [Copyright &y& Elsevier]

Abstract: Reaction of pristimerin with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) resulted in a biomimetic-type coupling leading to xuxuarines Eα and Eβ and not the previously reported Rzedowskia bistriterpenoids I and II suggesting that the structures proposed for these natural products need revision. A product obtained in this reaction by an unusual Diels-Alder addition followed by retro-Diels-Alder-type elimination was characterized as pristimerin dicyanophenalenedione. Complete 1H, and 13C NMR spectral assignments of xuxuarines Eα and Eβ have been made by the application of 1D and 2D NMR techniques. [Copyright &y& Elsevier]

Abstract: Bioactivity-guided fractionation of a cytotoxic extract of Aspergillus tubingensis, a fungal strain occurring in the rhizosphere of the Sonoran desert plant, Fallugia paradoxa, afforded a dimeric naphtho-γ-pyrone asperpyrone D, nine known naphtho-γ-pyrones, funalenone, and the cytotoxic cyclic penta-peptide, malformin A1. [Copyright &y& Elsevier]

Abstract: Bioassay-guided fractionation of a cytotoxic EtOAc extract of the fungal strain, Chaetomium globosum, inhabiting the rhizosphere of the Christmas cactus, Opuntia leptocaulis, of the Sonoran desert afforded a new dihydroxanthenone, globosuxanthone A (1), a new tetrahydroxanthenone, globosuxanthone B (2), two new xanthones, globosuxanthone C (3) and D (4), 2-hydroxyvertixanthone (5), and two known anthraquinones (6 and 7). The structures of the new compounds 1–4 were elucidated by NMR and MS techniques, and the relative stereochemistry of 1 was determined by X-ray crystallographic analysis. Of the compounds encountered, 1 was found to exhibit strong cytotoxicity against a panel of seven human solid tumor cell lines, disrupt the cell cycle leading to the accumulation of cells in either G2/M or S phase, and induce classic signs of apoptosis. [Copyright &y& Elsevier]

Incorporation of the epigenetic modifier suberoylanilide hydroxamic acid (SAHA) into a potato dextrose broth culture of the endophytic fungus Aspergillus sp. AST0006 affected its polyketide biosynthetic pathway providing two new 3-(4-oxopyrano)-chromen-2-ones, aspyranochromenones A (1) and B (2), and the isocoumarin, (−)-6,7-dihydroxymellein (3). Eight additional metabolites (4 – 11) and two biotransformation products of SAHA (12 – 13) were also encountered. The planar structures and relative configurations of the new metabolites 1 – 2 were elucidated with the help of high-resolution mass, 1D and 2D NMR spectroscopic data and the absolute configurations of 1 – 3 were determined by comparison of experimental and calculated ECD data. Possible biosynthetic pathways to 1 and 2 are presented. Image 1 • The secondary metabolites of Aspergillus sp. AST0006 cultured with the epigenetic modifier SAHA were investigated. • Incorporation of SAHA enhanced production of metabolites and afforded new compounds aspyranochromenones A and B. • Aspyranochromenones A and B contain a new carbon skeleton, despite numerous metabolites are known from Aspergillus spp. [ABSTRACT FROM AUTHOR]