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.

Keywords: Cytotoxicity; ergochromes; fungus; resorcylic acid lactones; secalonic acids.

Figure 1

Compounds 1–16 from S. terrestris (MSX45109).

Figure 2

Comparison of the experimental ECD spectra of secalonic acids A (1), E (2), and G (3) [0.03 mM CHCl₃, cell length 2 cm].

Figure 3

Experimental and calculated ECD spectra for penicillixanthone A (4) [0.05 mM, CHCl₃, cell length 2 cm].

Figure 4

Key COSY, HMBC, and NOESY correlations of 5–10 and 16. Based on the NOESY correlations, Gaussian 09 was used for ground state mechanics optimization to generate the structures shown on the right.

Figure 5

Experimental and calculated ECD spectra for penicillixanthone B (5) [0.06 mM, CHCl₃, cell length 2 cm].

Figure 6

Experimental ECD spectra of 11-deoxyblennolide D (7) [0.16 mM] and paecilin B (8) [0.56 mM, CHCl₃, cell length 2 cm].

Figure 7

Experimental and calculated ECD spectra for 11-deoxyblennolide D (7) [0.16 mM] and paecilin B (8) [0.56 mM, CHCl₃, cell length 2 cm].

Figure 8

Experimental and calculated ECD spectra for blennolide I (9) [0.06 mM, CHCl₃, cell length 2 cm].

Figure 9

Experimental and calculated ECD spectra for blennolide J (10) [0.17 mM, CHCl₃, cell length 2 cm].

Figure 10

Δδ_H values [Δδ (in ppm) = δ_S − δ_R] obtained for (S)- and (R)-MTPA esters (16a and 16b, respectively) of pyrenomycin (16) in pyridine-d₅.