Phytochemical investigation of the leaves of Icacina oliviformis led to the isolation of nine previously undescribed seco-(9β-H)-pimarane diterpenoids (1-9), along with two biosynthetic precursors (10 and 11). Their structures were elucidated using extensive NMR, HRESIMS, ECD (including Rh2(OCOCF3)4-induced ECD), and single-crystal X-ray diffraction analyses. Compound 1 represents the first natural 3,17-di-nor-pimarane, featuring a novel 2-oxaspiro4.5decan-3-one core fused to γ-butyrolactone and benzofuran units. Compounds 2-9 define a new structural subclass of naturally occurring 3,4-seco-17-nor-pimaranes. In the multicell line screening, compound 9 showed superior potency and selectivity against HT-29 (IC50 = 5.32 μM) and SW620 (IC50 = 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 9 induced apoptosis in HT-29 cells via ROS-driven selective activation of the ATF6-CHOP pathway.
Xu et al. (2026) studied this question.