Dimeric progestins from rhizomes of Ligusticum chuanxiong

(3 Z′)-(3a′ R,6′ R,3 R,6 R,7 R)-3,8-dihydro-6.6′,7.3a′-diligustilide was isolated from rhizomes of the “utero-tonic” Chinese medicinal plant Ligusticum chuanxiong. This dimeric phthalide strongly (EC 50 ∼ 90 nM) and specifically activated the progesterone receptor. Five dimeric phthalides were isolated from rhizomes of Ligusticum chuanxiong and their structures deduced based on spectral data. All compounds and their parent extracts were assessed for progesterone-like activity using a progesterone receptor driven reporter-gene bioassay. Among all the compounds, riligustilide, displayed weak progesterone-like activity (EC 50 ∼ 81 μM), whereas, (3 Z′)-(3a′ R,6′ R,3 R,6 R,7 R)-3,8-dihydro-6.6′,7.3a′-diligustilide ( M r: 382, EC 50 ∼ 90 nM), was found to be a potent and specific activator of the progesterone receptor. Levistolide A, although having a very similar plenary structure, was inactive indicating the importance of stereochemistry of chiral centers and flexibility of butylidene side chain for progestogenic activity. These bioactive phthalides and their parent extracts (EC 50 ∼ 8 μg/ml) may have utility for treatment of conditions requiring progesterone action.