| Summary: | Eighteen scalarane sesterterpenoids (<b>1</b>–<b>18</b>), including eight new derivatives (<b>1</b>–<b>8</b>), were isolated from the sponge <i>Hyrtios erectus</i> (family Thorectidae), the extract of which showed cytotoxicity against the HeLa and MCF-7 cell lines. Of the new derivatives, six compounds (<b>1</b>–<b>6</b>) were found to contain a γ-hydroxybutenolide moiety capable of reversible stereoinversion at the hydroxylated carbon center. Under the influence of other adjacent functional groups, each derivative exhibited a different stereochemical behavior, which was fully deduced by ROESY experiments. All the isolated compounds were examined for their cytotoxicity by MTS assay using staurosporine as a positive control (IC<sub>50</sub> 0.18 and 0.13 μΜ against HeLa and MCF-7 cells, respectively), and they were found to show weak growth inhibitory activities against HeLa and MCF-7 cells, with a minimal IC<sub>50</sub> value of 20.0 μΜ. The compounds containing a γ-hydroxybutenolide moiety (<b>1</b>–<b>3</b>, <b>10</b>, <b>12</b>) showed cytotoxicity, with IC<sub>50</sub> values ranging from 24.3 to 29.9 μΜ, and the most potent derivative was heteronemin (<b>16</b>). Although the cytotoxicities of isolated compounds were insufficient to discuss the structure–activity relationship, this research could contribute to expanding the structural diversity of scalaranes and understanding the stereochemical behavior of γ-hydroxybutenolides.
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