Absolute configuration of antifibrotic (+)-episesamin isolated from Lindera obtusiloba BLUME

Fractionation of a 70% ethanolic extract from twigs of Lindera obtusiloba BLUME (Japanese spicebush, Tohaku) yielded five fractions of different polarity. The antifibrotic activity within the chloroform phase was best assessed by an in vitro bioassay using rat hepatic stellate cell (HSC) proliferation and their autocrine transforming growth factor beta (TGF-beta) expression as sensitive fibrosis-associated read out. Chromatography of the chloroform extract on Sephadex LH-20 or liquid-liquid extractions yielded a crystalline compound as an active principle, which was identified from NMR and ESI-MS analyses, its melting point, and its optical rotation as (7S,7'R,8R,8'R)-3,4:3',4'-bis(methylenedioxy)-7,9':7',9-diepoxy-lignane [(+)-episesamin]. X-Ray diffraction confirmed the structure and provided, for the first time, directly its absolute configuration. (+)-Episesamin blocked proliferation and the profibrotic autocrine TGF-beta expression HSC without significant cytotoxicity.