Isolation and biomimetic synthesis of acylphloroglucinol meroterpenoids as anti-breast cancer agents from <i>Dryopteris crassirhizoma</i>

Two new acylphloroglucinol-nerolidol meroterpenoids (APNMs) [(±)-1 and (±)-2], with a skeleton of mixed sesquiterpene and dimeric acylphloroglucinol biosynthetic origin, were isolated from the medicinal pteridophyte <i>Dryopteris crassirhizoma</i>. Inspired by the proposed biosynthetic pathway, we initially completed the biomimetic syntheses of eight optically active <i>Dryopteris</i> APNMs (1-8) in a one-pot domino reaction. The structures of APNMs 1-8 including their absolute configurations were unambiguously established by a combination of NMR analysis, ECD calculations, and synthetic methods. Furthermore, an underlying method based on NMR data to assign the stereochemistry of the long-chain alcohol moieties in APNMs was revealed. Anti-triple negative breast cancer (anti-TNBC), antifungal and antibacterial activities of the synthetic meroterpenoids were evaluated. All tested compounds exhibited cytotoxicity against TNBC cells MDA-MB-231 with IC₅₀ values in the range of 1.22-27.43 μM, with (-)-8 being the most potent antitumor agent (IC₅₀: 0.48 μM; selectivity index: 32.04). This study resulted in the biomimetic synthesis of APNMs for the first time and positioned APNMs from <i>D</i>. <i>crassirhizoma</i> as a new class of promising candidates for the development of new anti-TNBC drugs.