Diketopiperazine and Diphenylether Derivatives from Marine Algae-Derived Aspergillus versicolor OUCMDZ-2738 by Epigenetic Activation

Abstract

A chemical-epigenetic method was used to enhance the chemodiversity of a marine algicolous fungus. Apart from thirteen known compounds, (+)-brevianamide R ((+)-<b>3</b>), (‒)-brevianamide R ((‒)-<b>3</b>), (+)-brevianamide Q ((+)-<b>4</b>), (‒)-brevianamide Q ((‒)-<b>4</b>), brevianamide V ((+)-<b>5</b>), brevianamide W ((‒)-<b>5</b>), brevianamide K (<b>6</b>), diorcinol B (<b>7</b>), diorcinol C (<b>8</b>), diorcinol E (<b>9</b>), diorcinol J (<b>10</b>), diorcinol (<b>11</b>), 4-methoxycarbonyldiorcinol (<b>12</b>), two new compounds, (+)- and (‒)-brevianamide X ((+)- and (‒)- <b>2</b>)), as well as a new naturally occurring one, 3-[6-(2-methylpropyl)-2-oxo-1<i>H</i>-pyrazin-3-yl]propanamide (<b>1</b>), were isolated from chemical-epigenetic cultures of <i>Aspergillus versicolor</i> OUCMDZ-2738 with 10 µM vorinostat (SAHA). Compared to cultures in the same medium without SAHA, compounds <b>1</b>⁻<b>4</b>, <b>8</b>, <b>9</b>, <b>11</b>, and <b>12</b> were solely observed under SAHA condition. The structures of these compounds were elucidated based on spectroscopic analysis, specific rotation analysis, ECD, and X-ray crystallographic analysis. (±)-<b>3</b>, (±)-<b>4</b>, and (±)-<b>5</b> were further resolved into the corresponding optically pure enantiomers and their absolute configurations were determined for the first time. Compounds <b>11</b> and <b>12</b> showed selective antibacterial against <i>Pseudomonas aeruginosa</i> with a minimum inhibitory concentration (MIC) of 17.4 and 13.9 μM, respectively. Compound <b>10</b> exhibited better α-glucosidase inhibitory activity than the assay control acarbose with IC₅₀ values of 117.3 and 255.3 μM, respectively.