Biosynthetically Distinct Cytotoxic Polyketides from <i>Setophoma terrestris</i>

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 <i>Setophoma terrestris</i> (MSX45109) using bioactivity-directed fractionation as part of a search for anticancer leads from filamentous fungi. Of these, six were new: penicillixanthone B (<b>5</b>), blennolide H (<b>6</b>), 11-deoxy blennolide D (<b>7</b>), blennolide I (<b>9</b>), blennolide J (<b>10</b>), and pyrenomycin (<b>16</b>). The known compounds were: secalonic acid A (<b>1</b>), secalonic acid E (<b>2</b>), secalonic acid G (<b>3</b>), penicillixanthone A (<b>4</b>), paecilin B (<b>8</b>), aigialomycin A (<b>11</b>), hypothemycin (<b>12</b>), dihydrohypothemycin (<b>13</b>), pyrenochaetic acid C (<b>14</b>), and nidulalin B (<b>15</b>). The structures were elucidated using a set of spectroscopic and spectrometric techniques; the absolute configurations of compounds <b>1</b>-<b>10</b> 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 <b>16</b>. The cytotoxic activities of compounds (<b>1</b>-<b>15</b>) were evaluated using the MDA-MB-435 (melanoma) and SW-620 (colon) cancer cell lines. Compounds <b>1</b>, <b>4</b>, and <b>12</b> 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 <b>3</b> and <b>5</b> showed promising activity against the Gram-positive bacterium <i>Micrococcus luteus</i> with MIC values of 5 and 15 μg/mL, respectively.