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

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

  • Eur J Med Chem. 2025 Jul 5:291:117676. doi: 10.1016/j.ejmech.2025.117676.
Ruihan Zhang 1,  Zhao Wu 2,  Hairong Wang 1,  Minghui Ji 2,  Tianze Shen 1,  Linhan Yang 2,  Yiming Li 1,  Jialing Yu 2,  Yinqiao Huang 1,  Lingyu Li 2,  Zihan Xu 1,  Yuwen Sheng 3,  Xiaoli Li 1,  Fei Wang 4,  Weilie Xiao 5
Affiliations

Affiliations

  • 1 Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Characteristic Plant Extraction Laboratory; Yunnan Key Laboratory of Research and Development for Natural Products; School of Chemical Science and Technology; School of Pharmacy, Yunnan University, Kunming, 650500, China.
  • 2 Center for the Utilization of Biological Resources, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 3 Center for the Utilization of Biological Resources, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, China.
  • 4 Center for the Utilization of Biological Resources, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, China. Electronic address: wangfei@cib.ac.cn.
  • 5 Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education; Yunnan Characteristic Plant Extraction Laboratory; Yunnan Key Laboratory of Research and Development for Natural Products; School of Chemical Science and Technology; School of Pharmacy, Yunnan University, Kunming, 650500, China. Electronic address: xiaoweilie@ynu.edu.cn.
PMID: 40279767 DOI: 10.1016/j.ejmech.2025.117676
Abstract

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.

Keywords

Dicer; Liver cancer; Pharmacophore; Target; Upregulation; metastasis; microRNA.

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