Antiplasmodial Asperterpenoids from Two <i>Aspergillus oryzae</i> Transformants with Heterologous Expression of Sesterterpene Genes

Abstract

The synthetic biology approach enables efficient and directional mining of target compounds during drug discovery. Ten new asperterpenoids (<b>6</b>-<b>15</b>) and five known analogues (<b>1</b>-<b>5</b>), possessing a rare 5/7/3/6/5 skeleton, were obtained from two <i>Aspergillus oryzae</i> transformants with heterologous expression of a terpene cyclase gene <i>AstC</i> with one or two P450 genes <i>AstB</i>/<i>A</i> under the guidance of molecular networking. Their planar structures were determined by 1D and 2D NMR and HR-ESI-MS. The absolute configurations of compounds <b>6</b> and <b>9</b>-<b>13</b> were determined by single crystal X-ray diffraction, and those of compounds <b>7</b>-<b>8</b> and <b>14</b>-<b>15</b> were compared with the ECD of known compounds. Seven of all the compounds are the first asperterpenoid oxidation products at C-17 or at C-25. In bioassay, compounds <b>1</b>-<b>2</b>, <b>4</b>-<b>5,</b> and <b>6</b>-<b>8</b> displayed moderate to strong eliminating activities against chloroquine-sensitive strain (<i>P.f.</i>3<i>D</i>7) with EC₅₀ values ranging from 2.1 to 19.3 μM. The structure-activity relationship (SAR) was discussed, which showed that substituents at C-3, C-11, C-17, C-18, and C-23 of asperterpenoids significantly affected anti-plasma parasite activity.