Involucratusins A–H: Unusual Cadinane Dimers from Stahlianthus involucratus with Multidrug Resistance Reversal Activity

摘要

Three novel cadinane dimers, involucratusins A–C (>1–>3), five unique nor-cadinane-dimers, involucratusins D–H (>4–>8), together with a known compound (>9) were isolated from the rhizomes of Stahlianthus involucratus. Their challenging structures and absolute configurations were determined by spectroscopic data, CD experimentation, chemical conversions and single-crystal X-ray diffraction. Compounds >1–>3 are unusual cadinane dimers with new connection and novel cores. Compound >4 is a unique nor-cadinane-dimer, and >5 and >6 are two pairs of hemiketal racemates with novel dinor-cadinane-dimer backbone. Compounds >7 and >8 represent unusual dodecanor-cadinane-dimer and tetradecanor-cadinane-dimer carbon skeletons, respectively. The possible biogenetic pathways of >1–>8 were proposed, involving nucleophilic addition, SN2 nucleophilic displacement, [3 + 3] benzannulation, oxidative cleavage, decarboxylation, and oxidative phenol coupling reactions. Multidrug resistance (MDR) reversal activity assay of the isolates were evaluated in doxorubicin-resistant human breast cancer cells (MCF-7/DOX). The combined use of these novel cadinane dimers at a concentration of 10 μM increased the cytotoxicity of doxorubicin by 2.2–5.8-fold. It is the first report about the MDR reversal activity of cadinane dimers.