In Vitro and In Silico Insights into the Antiproliferative Activity of Sesquiterpenes from Dittrichia viscosa (L.) Greuter

Four sesquiterpenes, namely tomentosin, 11α,13-dihydrotomentosin, inuviscolide, and α-costic acid, were isolated from the aerial parts of the medicinal plant Dittrichia viscosa (L.) Greuter and evaluated for antiproliferative activity against HCT116 colorectal and A549 lung cancer cells. All compounds reduced cell viability in a concentration-dependent manner, with tomentosin and inuviscolide exhibiting the greatest activity among the tested compounds and IC50 values in the moderate micromolar range. Evaluation in non-malignant human neonatal dermal fibroblasts (HDFn) revealed compound- and cancer-type-dependent selectivity, with inuviscolide showing greater selectivity toward HCT116 cells and tomentosin showing moderate selectivity toward both cancer cell lines. In silico ADMET and DFT analyses characterized the predicted drug-likeness, pharmacokinetic, toxicity-related, and electronic properties of the compounds, particularly tomentosin and inuviscolide. Network pharmacology prioritized STAT3, ESR1, and PTGS2 as candidate hub targets associated with both cancer types, while enrichment analyses identified pathways related to tumor proliferation, inflammation, immune regulation, and cellular stress. Noncovalent molecular docking, 200 ns molecular dynamics simulations, and MM/GBSA calculations supported possible modeled interactions of tomentosin and inuviscolide with these proteins, with tomentosin displaying the most favorable predicted binding profile. Covalent docking further identified structurally feasible STAT3 CYS687-linked poses with the two sesquiterpenes, although covalent adduct formation and direct target engagement remain to be experimentally validated. Overall, the integrated findings prioritize tomentosin and inuviscolide as D. viscosa-derived natural-product scaffolds with moderate antiproliferative activity for further structural optimization, selectivity assessment, and experimental mechanistic validation.