Structural optimization and pharmacological evaluation of diphenyl amine esters as anti-hepatocellular carcinoma agents by targeting TAR RNA-binding protein 2.

Hepatocellular Carcinoma (HCC), a leading cause of cancer-related death in the world, urgently requires novel therapeutic strategies and drug targets. The TRBP-Dicer complex plays a critical role in miRNA biosynthesis, which can be regulated by small molecules to exert anti-cancer effects. This study presented the structural modification of the natural product (-)-Gomisin M1(GM), resulting in the synthesis of 37 derivatives with a diphenyl amine ester scaffold. Several of these derivatives exhibited enhanced modulation of miRNA biogenesis compared to GM. Notably, derivative 13j displayed improved binding affinity to TRBP and greater efficacy in modulating miRNA biosynthesis, as well as anti-HCC activity in vitro and in vivo. Further investigation revealed that 13j induced apoptosis and pyroptosis while inhibiting the epithelial-to-mesenchymal transition process in HCC cells. In terms of druggability, 13j possesses favorable drug-likeness and a promising safety profile. These findings provide a promising scaffold with potent activity and low toxicity, offering a foundation for the development of miRNA-based therapeutic strategies for HCC.