C‑20 Diterpenoid Alkaloids with PD-L1 Inhibitory Activity from the Roots of Aconitum coreanum.

Fifteen previously unreported diterpenoid alkaloids, named aconicorines A-O (1-15), and 13 known diterpenoid alkaloids (16-28) were isolated from the roots of Aconitum coreanum. Their structures and configurations were determined by comprehensive spectroscopic analysis including HRMS, NMR, and single-crystal X-ray diffraction. Structurally, all new compounds are classic C20-hetisine-type diterpenoid alkaloids with various oxidation sites. Among them, aconicorines A-D (1-4) are unique C20-diterpenoid alkaloids containing a rare sulfonate group. Bioassay results showed that 1, 7, 13-17, and 20 dose-dependently inhibited the PD-L1 protein expression at 2.5-20 μM in MDA-MB-231 cells. Furthermore, immunofluorescence staining confirmed the inhibitory effect of 7, 14, 15, and 17 on PD-L1 expression. These findings first demonstrated the effects of C20-diterpenoid alkaloids on PD-L1 expression and suggested that C20-diterpenoid alkaloids are a new type of PD-L1 modulators.