Biosynthetically Distinct Cytotoxic Polyketides from Setophoma terrestris

Abstract

Sixteen polyketides belonging to diverse structural classes, including monomeric/dimeric tetrahydroxanthones and resorcylic acid lactones, were isolated from an organic extract of a fungal culture Setophoma terrestris (MSX45109) using bioactivity-directed fractionation as part of a search for anticancer leads from filamentous fungi. Of these, six were new: penicillixanthone B (5), blennolide H (6), 11-deoxy blennolide D (7), blennolide I (9), blennolide J (10), and pyrenomycin (16). The known compounds were: secalonic acid A (1), secalonic acid E (2), secalonic acid G (3), penicillixanthone A (4), paecilin B (8), aigialomycin A (11), hypothemycin (12), dihydrohypothemycin (13), pyrenochaetic acid C (14), and nidulalin B (15). The structures were elucidated using a set of spectroscopic and spectrometric techniques; the absolute configurations of compounds 1–10 were determined using ECD spectroscopy combined with time-dependent density functional theory (TDDFT) calculations, while a modified Mosher’s ester method was used for compound 16. The cytotoxic activities of compounds (1–15) were evaluated using the MDA-MB-435 (melanoma) and SW-620 (colon) cancer cell lines. Compounds 1, 4, and 12 were the most potent with IC50 values ranging from 0.16 to 2.14 μM. When tested against a panel of bacteria and fungi, compounds 3 and 5 showed promising activity against the Gram-positive bacterium Micrococcus luteus with MIC values of 5 and 15 μg/mL, respectively.

Chemoinformatic Expedition of the Chemical Space of Fungal Products

“…Based on previous studies and as part of our continued effort to quantify the chemical diversity of fungal isolates [6], herein we expand the analysis to a larger set of 207 compounds described by our group [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] that represent twice the size of the dataset analyzed in 2012. In the current analysis, we employed molecular fingerprints as distinct molecular representations not analyzed in the previous study; also we emphasized the evaluation of molecular complexity that may have a significant impact in drug discovery endeavors, since this feature has been associated with target selectivity (and potential toxicity).…”

“…The largest fragments were kept, duplicates in each dataset were removed and all molecules with molecular weight (MW) over 1000 were excluded. The in-house library of fungal metabolites with 207 compounds (referred to hereafter as 'FUNGI') [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] was compared with the following five reference collections: 2249 compounds based on the Flavor and Extract Manufacturers Association of the United States GRAS list, updated to GRAS 27 (hereafter referred to as 'GRAS') [24,30]; FDA drugs obtained from DrugBank [31] containing: 76 drugs approved to treat cancer (hereafter referred to as 'FDA-ONC') and 1399 nononcological drugs (hereafter referred to as 'FDA-NONC'); 713 drugs in clinical trials reported by the Therapeutic Target Database [32] (hereafter referred to as 'CLINIC'); and 850 compounds from a commercial collection focused on epigenetic targets, available at Selleckchem (hereafter referred to as 'GENERAL') [33]. Supplementary Table 1 summarizes the number of duplicate molecules found in the initial datasets.…”

Syntheses of Dimeric Tetrahydroxanthones with Varied Linkages: Investigation of “Shapeshifting” Properties

“…NMR spectra and α D values for (−)- 2 were found to be identical to those reported for the natural sample. 5a,d …”

“…4 In addition to the 2,2′-linked dimeric natural products, 2,4′- and 4,4′-linked secalonic acids are also found in nature. For example, the 2,4′-linked isomer penicillixanthone A ( 2 ) 5 and the 4,4′-linked secalonic acid E (talaroxanthone, 4 ) 6 have recently been isolated and characterized (Figure 1). In addition to the secalonic acids, biaryl linkage variation has been observed in related natural products.…”

Chemoselective fluorination and chemoinformatic analysis of griseofulvin: Natural vs fluorinated fungal metabolites

“…60–62 Briefly, a fresh culture of the fungus was grown on a malt extract slant. Subsequently, a small agar plug with mycelium was inoculated in a liquid medium consisting of 2% soy peptone, 2% dextrose, and 1% yeast extract (YESD media).…”