Phytochemical study of : isolation, antiproliferative activity, and computational mechanistic insights of tigliane diterpenes against colorectal cancer.

[CONTEXT] Colorectal cancer is the third most common and second deadliest cancer worldwide. Late diagnosis, poor outcomes in metastatic cases, and multidrug resistance emphasize the need for new therapies.

[OBJECTIVE] This study aimed to isolate bioactive compounds from Zoll. ex Miq. (Euphorbiaceae), evaluate their antiproliferative effects on colorectal cancer cells, and identify mechanisms through network pharmacology and molecular docking.

[MATERIALS AND METHODS] Compounds were isolated by chromatographic separations, and the structures were elucidated by NMR and HRESIMS. The antiproliferative activity was measured by MTT assay. DFT calculations were performed in ORCA 6.1.0. Network pharmacology was used to identify targets and pathways, molecular docking with AutoDock Vina was used to determine binding affinities, and pkCSM was applied to predict pharmacokinetics and toxicity.

[RESULTS] 7β-Hydroxysitosterol (), 7α-hydroxysitosterol (), 12--palmitoyl-phorbol-13-acetate (), 12--palmitoyl-7-oxo-5-ene-phorbol-13-acetate (), cerevisterol (), and β-sitosterol-3--glucoside () were isolated from . Compound exhibited the highest activity against Colo 205 (IC 3.58 ± 0.37 μM) and Colo 320 cells (IC 6.06 ± 1.70 μM) and higher DFT stability. Network pharmacology and docking study revealed kinase-specific targeting (STAT3, JUN, PRKCA, GSK3β), with preferentially binds PRKCA/GSK3β, whereas favors STAT3/JUN. The pkCSM prediction server predicted good oral bioavailability, CYP3A4 metabolism, limited CNS penetration, and acceptable toxicity for both diterpenes.

[DISCUSSION AND CONCLUSIONS] Six compounds were isolated from with exhibiting antiproliferative activity through PRKCA and GSK3β modulation. These findings provide the first phytochemical and mechanistic evidence that support as a promising source of active anti-colon cancer leads.