Sorbicillinoid analogs with cytotoxic and selective anti-Aspergillus activities from Scytalidium album

Abstract

As part of an ongoing project to explore filamentous fungi for anticancer and antibiotic leads, eleven compounds were isolated and identified from an organic extract of the fungus Scytalidium album (MSX51631) using bioactivity-directed fractionation against human cancer cell lines. Of these, eight were a series of sorbicillinoid analogues (1–8), of which four were new [scalbucillin A (2), scalbucillin B (3), scalbucillin C (6), and scalbucillin D (8)], two were phthalides (9–10), and one was naphthalenone (11). Compounds (1–11) were tested in the MDA-MB-435 (melanoma) and SW-620 (colon) cancer cell lines. Compound 1 was the most potent with IC50 values of 1.5 and 0.5 μM, respectively, followed by compound 5, with IC50 values of 2.3 and 2.5 μM at 72 h. Compound 1 showed a 48-h IC50 value of 3.1 μM when tested against the lymphocytic leukemia cell line OSU-CLL, while the nearly identical compound 5 had almost no activity in this assay. Compounds 1 and 5 showed selective and equipotent activity against Aspergillus niger with minimum inhibitory concentration values of 0.05 and 0.04 μg/ml (0.20 and 0.16 μM), respectively. The in vitro hemolytic activity against sheep erythrocytes of compounds 1 and 5 was investigated and were found to provoke 10% hemolysis at 52.5 and 45.0 μg/ml, respectively, indicative of a promising safety factor.

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.…”

Sorbicillinoids from Fungi and Their Bioactivities

“…NRRL32148 from the surface of stromata of Hypoxylon truncatum formed on a dead hardwood branch [33] Scytalidium album MSX51631 from a soil sample [12] Scytalidium sp. FY as an immunizing commensal of Douglasfir utility poles [34] Scalbucillin A (11) Scytalidium album MSX51631 from a soil sample [12] Scalbucillin B (12) Scytalidium album MSX51631 from a soil sample [12] …”

“…NRRL32148 from the surface of stromata of Hypoxylon truncatum formed on a dead hardwood branch [33] Scytalidium album MSX51631 from a soil sample [12] …”

“…In 2011, Harned and Volp reviewed the structures of 62 sorbicillinoids [1]. Since then, many new members of this family were isolated and great progress has been made [4,[10][11][12][13]. According to the structural features, sorbicillinoids can be divided into four groups: monomeric sorbicillinoids, bisorbicillinoids, trisorbicillinoids, and hybrid sorbicillinoids.…”