Kaurepenoid A, a 2-nor-ent-kaurane diterpenoid with P-glycoprotein-mediated reversal of multidrug resistance activity from the fungus Bipolaris sp.

Chemical research on the fungus Bipolaris sp. led to the identification of seven ent -kaurane diterpenoids, kaurepenoids A–G ( 1 – 7 ), marking the first isolation of such diterpenoids from this genus. Kaurepenoids A–F ( 1 – 6 ) represent the first 2- nor - ent -kaurane diterpenoids with a fused 5/6/6/5 tetracyclic ring system. Kaurepenoid G ( 7 ) bears a rare 2,3-epoxy- ent -kaurane skeleton. Their structures and absolute configurations were elucidated by NMR, ECD calculations, and single-crystal X-ray diffraction analyses. Putative biosynthetic pathways for kaurepenoids A–F were proposed. Furthermore, the derivatization of both kaurepenoids B and C as starting materials afforded five derivatives ( 8 – 12 ). Among these compounds, kaurepenoid A could increase the efficacy of anticancer drug paclitaxel (PTX) by 204-fold at 20 μmol·L −1 . Mechanistic investigation demonstrated that kaurepenoid A could inhibit the transport function of P-glycoprotein (P-gp) rather than affecting its expression, and the possible recognition mechanism was predicted by molecular docking.