Harperoids A–F, Complex Polyprenylated Acylphloroglucinols from <i>Harrisonia perforata</i> that Reverse Multidrug Resistance by Targeting ABC Transporter Function

Utilizing an LC/MS-MS-based feature-based molecular networking (FBMN) strategy, six undescribed PPAPs (<b>1</b>-<b>6</b>) characterized by an acetyl substituent at the C-1 position of their phloroglucinol scaffold, were efficiently isolated from the roots of <i>Harrisonia perforata</i>. Notably, compund <b>1</b> displays an unconventional 5/5/6/5 ring architecture, while compounds <b>5</b> and <b>6</b> represent the first case incorporating a benzofuran core and a geranyl-derived cyclohexanol unit. Their structures were unequivocally elucidated through comprehensive spectroscopic data analysis, TDDFT-ECD calculations, and X-ray crystallographic studies. Interestingly, compound <b>3</b> at 20 <i>μ</i>M exhibited negligible cytotoxicity but significantly potentiated the activity of paclitaxel against HCT-15 cells by 42.8-fold. Mechanistic studies further demonstrated that compound <b>3</b> did not significantly alter the expression levels of ATP-binding cassette (ABC) transporters, but potently inhibited the transport function of both ABCB1 and ABCG2. Molecular docking reveals that compound <b>3</b> stably binds to the central substrate-binding cavities of ABCB1 and ABCG2, with its binding primarily stabilized by hydrogen bonds and hydrophobic interactions.