Filicinic Acid-Based Meroterpenoids with Antiproliferative Activity against Prostate Cancer PC-3 Cells from <i>Dryopteris wallichiana</i>

Nine new structurally diverse filicinic acid-based meroterpenoids (<b>1</b>-<b>9</b>) with four kinds of carbon skeletons were isolated from the rhizomes of <i>Dryopteris wallichiana</i>. Their structures, including the absolute configurations, were elucidated by comprehensive analysis of spectroscopic data, quantum chemical calculations, and single-crystal X-ray diffraction. Structurally, compounds <b>1</b>-<b>4</b> feature an unprecedented 6/6/5/6/6/6 hexacyclic system with a rare oxaspiro[4.5]decane core linking the filicinic acid and <i>ent</i>-kaurane-type diterpene moieties. Compounds <b>5</b>-<b>6</b> are rare hybrids of filicinic acid and carotane-type sesquiterpene. Compound <b>7</b> is an unusual rearranged filicinic acid-carotane-type sesquiterpene meroterpenoid. Compounds <b>8</b>-<b>9</b> are two enantiomeric pairs of new meroterpenoids constructed by filicinic acid and a germarane-type sesquiterpene. A plausible biosynthetic pathway for the nine compounds was proposed. Notably, compounds <b>5</b>, <b>6</b>, (+)/(-)-<b>8</b>, and (+)/(-)-<b>9</b> were discovered to possess antiproliferative activity against PC-3 cells based on virtual screening, and in vitro bioassay. An interactive preprint version of the article can be found at https://www.authorea.com/doi/full/10.22541/au.172666991.17272585/v1.