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

Abstract

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.