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

Sesquiterpenoid dimers are some naturally occurring metabolites that have C30 cores, and originate biosynthetically from two sesquiterpenoid molecules1. Cadinane dimers, as one class of sesquiterpenoid dimers, are of considerable interest due to their ability to induce diverse biological activity (e.g. male antifertility, anticancer, antiviral, and anti-inflammatory)1. Of these naturally occurring cadinane dimers, most are derived from two units of the corresponding monomers by the free-radical coupling reaction1, however, rare example that formed by nucleophilic addition reaction have been reported. The occurrence of nor-cadinane-dimer is also surprisingly low, with the only two, aquatidial2 and parviflorene I3. Recently, we have reported three unprecedented cadinane dimers, involucratustones A–C4, from Stahlianthus involucratus, a folklore medicine to treat inflammation, pain, and fever5, as part of a continued program searching for novel terpenoids from Zingiberaceae plants6,7,8,9. These prompt us to perform a further phytochemical investigation on S. involucratus. As a result, three unusual cadinane dimers, involucratusins A–C (1–3) (Fig. 1), five novel nor-cadinane-dimers, involucratusins D–H (4–8), and a biosynthetically related known compound parviflorene D (9)3,10 were isolated and elucidated. Structurally, the architectures of 1–8 are different from the previously isolated cadinane dimers and nor-cadinane-dimers and represent five new carbon skeletons. Moreover, from the viewpoint of biosynthesis, the key biosynthesis reactions of cadinane dimers 1–3, nucleophilic addition, and nor-cadinane-dimers 5–8, oxidative cleavage, are extremely rare in the biosynthesis of cadinane dimers and norterpenoids, respectively. Herein are described the isolation, structure elucidation and possible biosynthesis of new metabolites 1–8, as well as MDR reversal activities of the compounds obtained. Figure 1 Structures of compounds 1–8.