Unprecedented nor-seco-diterpene lactones inhibited osteogenic differentiation of valve interstitial cells

The first examples of ent-atisane and ent-isopimarane diterpene lactones with an unusual 2,3-seco-2-nor-tetrahydro-2H-pyran-2-one nucleus, eufislactones A (1) and B (2), were isolated from the roots of Euphorbia fischeriana, together with a new (3) and fifteen known biosynthetic congeners (4-18). Their structures incorporating absolute configurations were elucidated via the comprehensive spectroscopic analyses, electronic circular dichroism (ECD) calculation, and single-crystal X-ray diffraction analyses. Biogenetically, compounds 1 and 2 were constructed by the plausible monomeric precursors, ent-atis-16-ene-3,14-dione (6) and ent-isopimara-8(14),15-dien-3-one (17), respectively, via key Baeyer-Villiger oxidation, decarboxylation, and semi-acetalization reactions to create a unique 2,3-seco-2-nor-tetrahydro-2H-pyran-2-one core. Our bioassays have revealed that eufislactone A (EFA, 1) displayed significant inhibitory effect on the osteogenic differentiation of human valvular interstitial cells (VICs), highlighting its potential as a preventive agent against the progression of human calcific aortic valve disease (CAVD).