Discovery of -(9β-H)-Pimarane Diterpenoids from with Synergistic Anti-Colorectal Cancer Activity.

Phytochemical investigation of the leaves of led to the isolation of nine previously undescribed -(9β-H)-pimarane diterpenoids (-), along with two biosynthetic precursors ( and ). Their structures were elucidated using extensive NMR, HRESIMS, ECD (including Rh(OCOCF)-induced ECD), and single-crystal X-ray diffraction analyses. Compound represents the first natural 3,17-di--pimarane, featuring a novel 2-oxaspiro[4.5]decan-3-one core fused to γ-butyrolactone and benzofuran units. Compounds - define a new structural subclass of naturally occurring 3,4--17--pimaranes. In the multicell line screening, compound showed superior potency and selectivity against HT-29 (IC = 5.32 μM) and SW620 (IC = 9.92 μM) cells compared to 5-fluorouracil (5-FU). Moreover, it exhibited strong synergy with 5-FU in both HT-29 cells (CI = 0.0904) and CRC patient-derived organoids (CI = 0.2903), suggesting a significant dose-reduction potential for 5-FU. Mechanistic studies revealed that compound induced apoptosis in HT-29 cells via ROS-driven selective activation of the ATF6-CHOP pathway.