| Summary: | Five hybrid polyketides (<b>1a</b>, <b>1b</b>, and <b>2</b>−<b>4</b>) containing tetramic acid core including a new hybrid polyketide, cladosin L (<b>1</b>), were isolated from the marine fungus <i>Cladosporium sphaerospermum</i> SW67, which was isolated from the marine hydroid polyp of <i>Hydractinia echinata</i>. The hybrid polyketides were isolated as a pair of interconverting geometric isomers. The structure of <b>1</b> was determined based on 1D and 2D NMR spectroscopic and HR-ESIMS analyses. Its absolute configuration was established by quantum chemical electronic circular dichroism (ECD) calculations and modified Mosher’s method. Tetramic acid-containing compounds are reported to be derived from a hybrid PKS-NRPS, which was also proved by analyzing our <sup>13</sup>C-labeling data. We investigated whether compounds <b>1</b>−<b>4</b> could prevent cell damage induced by cisplatin, a platinum-based anticancer drug, in LLC-PK1 cells. Co-treatment with <b>2</b> and <b>3</b> ameliorated the damage of LLC-PK1 cells induced by 25 μM of cisplatin. In particular, the effect of compound <b>2</b> at 100 μM (cell viability, 90.68 ± 0.81%) was similar to the recovered cell viability of 88.23 ± 0.25% with 500 μM <i>N</i>-acetylcysteine (NAC), a positive control.
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