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An In Vitro Enzymatic Assay to Measure Transcription Inhibition by GalliumIII and H3 5,10,15-trispentafluorophenylcorroles
Published on: March 18, 2015
Structural optimization and pharmacological evaluation of diphenyl amine esters as anti-hepatocellular carcinoma
Ruihan Zhang1, Zhao Wu2, Hairong Wang1
1Key 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.
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.
Insights
Researchers developed new compounds targeting miRNA biosynthesis for Hepatocellular Carcinoma (HCC). Derivative 13j showed potent anti-HCC effects by modulating miRNA, inducing cell death, and inhibiting cancer spread, offering a promising therapeutic strategy.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Hepatocellular Carcinoma (HCC) is a major global cancer burden needing new treatments.
- The TRBP-Dicer complex is vital for miRNA biosynthesis, a potential target for anti-cancer drugs.
Purpose of the Study:
- To synthesize and evaluate novel (-)-Gomisin M1 derivatives for modulating miRNA biosynthesis and anti-HCC activity.
- To identify potent compounds with improved efficacy and druggability for HCC therapy.
Main Methods:
- Structural modification of (-)-Gomisin M1 to create 37 derivatives.
- Assessing miRNA biosynthesis modulation, TRBP binding affinity, and in vitro/in vivo anti-HCC activity.
- Investigating mechanisms including apoptosis, pyroptosis, and epithelial-to-mesenchymal transition (EMT) inhibition.
Main Results:
- Several derivatives showed enhanced miRNA biosynthesis modulation compared to the parent compound.
- Derivative 13j demonstrated superior TRBP binding, miRNA modulation, and significant anti-HCC efficacy.
- 13j induced apoptosis and pyroptosis, and inhibited EMT in HCC cells, with favorable drug-likeness and safety.
Conclusions:
- The novel diphenylamine ester scaffold, exemplified by 13j, offers potent miRNA-modulating and anti-HCC activity.
- Derivative 13j represents a promising lead compound for developing novel miRNA-based HCC therapeutics.
- The findings support further development of 13j for its therapeutic potential and low toxicity in HCC treatment.
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