article · Organic Letters
Phytochemical investigation of the leaves of <i>Icacina oliviformis</i> led to the isolation of nine previously undescribed <i>seco</i>-(9β-H)-pimarane diterpenoids (<b>1</b>-<b>9</b>), along with two biosynthetic precursors (<b>10</b> and <b>11</b>). Their structures were elucidated using extensive NMR, HRESIMS, ECD (including Rh<sub>2</sub>(OCOCF<sub>3</sub>)<sub>4</sub>-induced ECD), and single-crystal X-ray diffraction analyses. Compound <b>1</b> represents the first natural 3,17-di-<i>nor</i>-pimarane, featuring a novel 2-oxaspiro[4.5]decan-3-one core fused to γ-butyrolactone and benzofuran units. Compounds <b>2</b>-<b>9</b> define a new structural subclass of naturally occurring 3,4-<i>seco</i>-17-<i>nor</i>-pimaranes. In the multicell line screening, compound <b>9</b> showed superior potency and selectivity against HT-29 (IC<sub>50</sub> = 5.32 μM) and SW620 (IC<sub>50</sub> = 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 <b>9</b> induced apoptosis in HT-29 cells via ROS-driven selective activation of the ATF6-CHOP pathway.
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DOI: 10.1021/acs.orglett.6c00495
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