Design, synthesis and evaluation of pterostilbene-indole hybrids as potential anticancer agents

Pterostilbene is a natural product that exhibits anticancer activity, primarily by targeting the jak/STAT3 signaling pathway. To enhance the anticancer efficacy of pterostilbene, a series of pterostilbene-indole hybrids were designed and synthesized via molecular hybridization with indole, aiming to develop novel STAT3 inhibitors, and preliminary structure-activity relationships (SAR) were established. Among them, 18q exhibited potent antitumor activity with IC₅₀ values of 1.84 ± 0.41 μM (C6 cells) and 4.81 ± 1.12 μM (A549 cells). Flow cytometry analysis revealed its ability to promote late-stage apoptosis. Additionally, 18q significantly suppressed tumor cell proliferation and migration, showing efficacy comparable to the positive control Vorinostat. It inhibited STAT3 phosphorylation, downregulated Bcl-2, and upregulated caspase-3, indicating apoptosis induction. The CETSA experiment showed that 18q could stabilize the thermal degradation of STAT3, proving that it was a direct inhibitor of STAT3. In conclusion, 18q is a promising STAT3 inhibitor with robust antitumor activity.