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

IF 6 2区 医学 Q1 CHEMISTRY, MEDICINAL
Ruihan Zhang , Zhao Wu , Hairong Wang , Minghui Ji , Tianze Shen , Linhan Yang , Yiming Li , Jialing Yu , Yinqiao Huang , Lingyu Li , Zihan Xu , Yuwen Sheng , Xiaoli Li , Fei Wang , Weilie Xiao
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引用次数: 0

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.

Abstract Image

Abstract Image

靶向TAR rna结合蛋白2的二苯胺酯抗肝癌药物结构优化及药理评价
肝细胞癌(HCC)是导致全球癌症相关死亡的主要原因之一,迫切需要新的治疗策略和药物靶点。TRBP-Dicer 复合物在 miRNA 的生物合成过程中发挥着关键作用,而小分子化合物可通过调节该复合物发挥抗癌作用。本研究介绍了对天然产物 (-)-Gomisin M1(GM)的结构改造,从而合成了 37 种具有二苯基胺酯支架的衍生物。与 GM 相比,其中几种衍生物对 miRNA 生物发生的调节作用有所增强。值得注意的是,13j 衍生物与 TRBP 的结合亲和力更强,在调节 miRNA 生物合成方面的功效更大,而且在体外和体内都具有抗HCC 活性。进一步研究发现,13j 在抑制 HCC 细胞上皮细胞向间质转化过程的同时,还能诱导细胞凋亡和热凋亡。在可药用性方面,13j 具有良好的药物相似性和安全性。这些发现为开发基于 miRNA 的 HCC 治疗策略奠定了基础。
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来源期刊
CiteScore
11.70
自引率
9.00%
发文量
863
审稿时长
29 days
期刊介绍: The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.
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