Discovery of Orally Effective Corydamine Derivatives Targeting Glutathione Metabolism to Sensitize Hepatocellular Carcinoma to Sorafenib

Abstract Sorafenib offers limited benefit in hepatocellular carcinoma (HCC). In this study, we designed and synthesized a series of novel corydamine derivatives and identified 8g as a lead compound with anti-HCC activity comparable to sorafenib. Mechanistic studies suggest that 8g targets glutathione reductase (GR), disrupting glutathione metabolism and NADPH homeostasis and weakening tumor redox defenses. Notably, the combination of 8g and sorafenib markedly enhanced ROS generation, inhibited HCC cell migration and invasion, and induced G2/M arrest and apoptosis, demonstrating strong synergistic anticancer activity. In addition, 8g showed favorable druggability, including good metabolic stability in human liver microsomes (T1/2 > 5 h), low hERG inhibition (IC50 > 50 μM), and high oral bioavailability (84.9%). In a Huh7 xenograft model, the combination achieved 61.0% tumor growth inhibition, significantly outperforming sorafenib alone (29.7%). These findings propose a redox-targeting strategy to sensitize HCC to sorafenib and highlight 8g as a promising anti-HCC lead.