Obionin B: an o-pyranonaphthoquinone decaketide from an unidentified fungus (MSX 63619) from the order Pleosporales

Abstract

A fungal extract (MSX 63619), from the Mycosynthetix library of over 50,000 fungi, displayed promising cytotoxicity against a human tumor cell panel. Bioactivity-directed fractionation led to the isolation of an o-pyranonaphthoquinone decaketide, which we termed obionin B (1). The structure of 1 was deduced via spectroscopic and spectrometric techniques. The IC50 value of 1 was moderate, ranging from 3 to 13 μM, depending on the cell line tested.

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.…”

Biosynthetically Distinct Cytotoxic Polyketides from Setophoma terrestris

“…[34] DNA extraction, PCR amplification, sequencing, and phylogenetic analyses were performed as described previously. [1b, 35] BLAST search in GenBank and the curated BOLD systems (http://www.boldsystems.org/index.php/IDS_OpenIdEngine) database, as well as Q-bank using ITS rDNA sequences suggested that MSX45109 shared high sequence similarity with several Centraalbureau voor Schimmelcultures (CBS) strains of Setophoma terrestris (Pleosporales, Ascomycota) with ≥80% query coverage and 99–100% sequence identity. The top BLAST matches were downloaded using Seaview v4.4.2.…”

“…[1] The organic extract of a solid phase culture of Setophoma terrestris (MSX45109), which was isolated from plant material collected in a mangrove habitat in 1989, showed potent cytotoxic activities against the SW-620 (colon) and MDA-MB-435 (melanoma) cancer cell lines (~91% and 100% inhibition of cell growth when tested at 20 μg/mL, respectively). Of the hundreds of cultures that have been investigated as part of this project, S. terrestris was intriguing due to the robust biosynthesis of 16 polyketides ( 1 – 16 ) of distinct structural classes.…”

“…These points are also critical for accurate and comprehensive dereplication studies of fungal metabolites, an area of growing prominence in the field. [1a, 3] Interestingly, a recent and comprehensive study reported a similar series of compounds albeit with opposite absolute configuration. [4] …”