Resveratrol Derivatives with a Urea Backbone Exert Anticancer Effects against Liver Cancer via Apoptosis Induction and Metastasis Inhibition

Hepatocellular carcinoma remains a fatal disease with a high metastasis risk. Matrix metalloproteinases (MMPs) are key mediators of metastasis and are potential therapeutic targets. Using a natural product derivatization strategy, we designed novel anticancer agents based on resveratrol─a dietary polyphenol found in grapes and other food sources with known MMP-suppressive effects. Although the resveratrol derivative amino-Res (<b>5</b>) showed promising <i>in vitro</i> activity, its poor metabolic stability limited its <i>in vivo</i> efficacy. To address this, we synthesized 14 urea-containing derivatives of amino-Res. Among them, compound <b>6k</b> exhibited improved metabolic stability and potent anticancer activity both <i>in vitro</i> and <i>in vivo</i>. Mechanism studies revealed that <b>6k</b> arrests the cell cycle in the G2/M phase, induces intrinsic apoptosis, and inhibits migration and invasion through MMP suppression. This work demonstrates the value of derivatizing dietary natural products for developing novel anticancer agents.