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

Abstract

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 Dryopteris crassirhizoma. Inspired by the proposed biosynthetic pathway, we initially completed the biomimetic syntheses of eight optically active Dryopteris 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 D. crassirhizoma as a new class of promising candidates for the development of new anti-TNBC drugs.