Discovery and evaluation of phenacrylanilide derivatives as novel potential anti-liver fibrosis agents
Discovery and evaluation of phenacrylanilide derivatives as novel potential anti-liver fibrosis agents
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作为新型潜在抗肝纤维化药物的苯丙烯酰苯胺衍生物的发现和评价
DOI：
10.1016/j.ejmech.2022.114685
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发表时间：
2022
影响因子：
6.7
通讯作者：
Tinghong Ye
中科院分区：
文献类型：
--
作者：
Lin Yue;Taixiong Xue;Xingping Su;Zhihao Liu;Hongyao Liu;Zui Tan;Cailing Gan;Yuting Xie;Tinghong Ye
肝纤维化是由慢性肝损伤引起的细胞外基质成分的过度沉积。目前，美国食品药品监督管理局还没有批准用于治疗肝纤维化的药物。在这里，我们报道了一系列具有苯丙烯酰苯胺骨架的新型化合物，它们可以有效抑制转移生长因子β 1（TGF-β 1）诱导的肝星状细胞（HSC）系LX-2的激活。其中，化合物42抑制TGF-β 1诱导的纤维化标志物（α-SMA和纤连蛋白）的上调，并且在体外显示出优异的安全性。此外，在四氯化碳（CCl4）诱导的肝纤维化模型中，30 mg/kg/天剂量的42通过口服给药3周有效地改善肝功能，恢复受损的肝脏结构，并减少胶原沉积，效果比曲尼司特更好。此外，在纤维化过程中，上皮-间充质转化（EMT）被化合物42抑制。同时，免疫微环境的失衡也可以得到有效的逆转。更有趣的是，化合物42延长了CCl 4小鼠的存活，并改善了CCl 4诱导的脾、肾、肺和心脏的损伤。总之，这些结果表明，42可能是治疗肝纤维化的潜在候选药物。苯丙烯酰苯胺衍生物抑制TGF-β 1诱导的肝星状细胞增殖和活化。·化合物42以较低的毒性抑制纤维化标志物表达。·在CCl4诱导的小鼠纤维化中，化合物42的施用改善了肝功能，减轻了纤维化，并抑制了肝星状细胞活化。·化合物42调节体内不平衡的免疫微环境。
Liver fibrosis is characterized by the excessive deposition of extracellular matrix components and results from chronic liver injury. At present, there is no approved drug for the treatment of liver fibrosis by the Food and Drug Administration. Here, we have reported a series of novel compounds with phenacrylanilide scaffolds that potently inhibit the transfer growth factor β1 (TGF-β1)-induced activation of LX-2, a hepatic stellate cell (HSC) line. Among them, compound 42 suppressed TGF-β1-induced upregulation of fibrotic markers (α-SMA and fibronectin) and showed excellent safety in vitro . Furthermore, in a carbon tetrachloride (CCl 4 ) -induced liver fibrosis model, 42 at a dose of 30 mg/kg/day through oral administration for 3 weeks effectively improved liver function, restored damaged liver structures, and reduced collagen deposition, with a greater effect than Tranilast . In addition, epithelial-mesenchymal transition (EMT) is inhibited by compound 42 in the process of fibrosis. Meanwhile, the imbalanced immune microenvironment could also be effectively reversed. More interestingly, compound 42 prolongs the survival of CCl 4 mice and ameliorates CCl 4 -induced injury to spleen, kidney, lung and heart. Altogether, these results suggest that 42 could be a potential drug candidate for the treatment of liver fibrosis. • Phenacrylanilide derivates inhibited TGF-β1- induced hepatic stellate cell proliferation and activation. • Compound 42 inhibited fibrotic markers expression with lower toxicity. • Administration of compound 42 improved liver function, alleviated fibrosis, and inhibited hepatic stellate cell activation in CCl 4 -induced mouse fibrosis. • Compound 42 regulated unbalanced immune microenvironment in vivo.