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 (5) showed promising in vitro activity, its poor metabolic stability limited its in vivo efficacy. To address this, we synthesized 14 urea-containing derivatives of amino-Res. Among them, compound 6k exhibited improved metabolic stability and potent Anticancer activity both in vitro and in vivo. Mechanism studies revealed that 6k 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.

cancer metastasis; hepatocellular carcinoma; pharmacokinetics; resveratrol derivatives; urea backbone.